HIGH MOLECULAR WEIGHT SURFACE PROTEINS OF NON-TYPEABLE HAEMOPHILUS

Abstract: High molecular weight surface proteins of non-typeable Haemophilus influenzae which exhibit immunogenic properties and genes encoding the same are described. Specifically, genes coding for two immunodominant high molecular weight proteins, HMW1 and HMW2, have been cloned, expressed and sequenced, while genes coding for high molecular proteins HMW3 and HMW4 have been cloned, expressed and partially sequenced.

Description: TITLE OF INVENTION HIGH MOLECULAR WEIGHT SURFACE PROTEINS OF NON-TYPEABLE HAEMOPHILUS FIELD OF INVENTION This invention relates to high molecular weight proteins of non-typeable haemophilus. BACKGROUND TO THE INVENTION Non-typeable Haemophilus influenzae are non- encapsulated organisms that are defined by their lack of reactivity with antisera against known H. influenzae capsular antigens. These organisms commonly inhabit the upper respiratory tract of humans and are frequently responsible for infections, such aε otitis media, sinusitis, conjunctivitis, bronchitis and pneumonia. Since these organisms do not have a polysaccharide capsule, they are not controlled by the present Haemophilus influenzae type b (Hib) vaccines, which are directed towards Hib bacterial capsular polysaccharides. The non-typeable strains, however, do produce surface antigens that can elicit bactericidal antibodies. Two of the major outer membrane proteins, P2 and P6, have been identified as targets of human serum bactericidal activity. However, it has been shown that the P2 protein sequence is variable, in particular in the non-typeable Haemophilus strains. Thus, a P2-based vaccine would not protect against all strains of the organism. There have previously been identified by Barenkamp et al (Pediatr. Infect. Pis. J.. 9:333-339, 1990) a group of high-molecular-weight (HMW) proteins that appeared to be major targets of antibodies present in human convalescent sera. Examination of a series of middle ear isolates revealed the presence of one or two such proteins in most strains. However, prior to the present invention, the structures of these proteins were unknown as were pure isolates of such proteins. SUMMARY OF INVENTION The inventors, in an effort to further characterize the high molecular weight (HMW) Haemophilus proteins, have cloned, expressed and sequenced the genes coding for two immunodominant HMW proteins (designated HMWl and HMW2) from a prototype non-typeable Haemophilus strain and have cloned, expressed and almost completely sequenced the genes coding for two additional immunodominant HMW proteins (designated HMW3 and HMW4) from another non-typeable Haemophilus strain. In accordance with one aspect of the present invention, therefore, there is provided an isolated and purified gene coding for a high molecular weight protein of a non-typeable Haemophilus strain, particularly a gene coding for protein HMWl, HMW2, HMW3 or HMW4, as well as any variant or fragment of such protein which retains the immunological ability to protect against disease caused by a non-typeable Haemophilus strain. In another aspect, the invention provides a high molecular weight protein of non-typeable Haemophilus influenzae which is encoded by these genes. BRIEF DESCRIPTION OF DRAWINGS Figure 1 is a DNA sequence of a gene coding for protein HMWl (SEQ ID NO: 1) ; Figure 2 is a derived amino acid sequence of protein HMWl (SEQ ID NO: 2) ; Figure 3 is a DNA sequence of a gene coding for protein HMW2 (SEQ ID NO: 3) ; Figure 4 is a derived amino acid sequence of HMW2 (SEQ ID NO: 4) ; Figure 5A shows restriction maps of representative recombinant phages which contained the HMWl or HMW2 structural genes, the locations of the structural genes being indicated by the shaded bars; Figure 5B shows the restriction map of the T7 expression vector pT7-7; Figure 6 contains the DNA sequence of a gene cluster for the h wl gene (SEQ ID NO: 5) , comprising nucleotides 351 to 4958 (ORF a) (as in Figure 1) , as well as two additional downstream genes in the 3' flanking region, comprising ORFs b, nucleotides 5114-6748 and c nucleotides 7062-9011; Figure 7 contains the DNA sequence of a gene cluster for the hmw2 gene (SEQ ID NO: 6) , comprising nucleotides 792 to 5222 (ORF a) (as in Figure 3) , as well as two additional downstream genes in the 3' flanking region, comprising ORFs b, nucleotides 5375-7009, and c, nucleotides 7249-9198; Figure 8 is a partial DNA sequence of a gene coding for protein HMW3 (SEQ ID NO: 7) ; Figure 9 is a partial DNA sequence of a gene coding for protein HMW4 (SEQ ID NO: 8) ; and Figure 10 is a comparison table for the derived amino acid sequence for proteins HMWl, HMW2, HMW3 and HMW4. GENERAL DESCRIPTION OF INVENTION The DNA sequences of the genes coding for HMWl and HMW2, shown in Figures 1 and 3 respectively, were shown to be about 80% identical, with the first 1259 base pairs of the genes being identical. The derived amino acid sequences of the two HMW proteins, shown in Figures 2 and 4 respectively, are about 70% identical. Furthermore, the encoded proteins are antigenically related to the filamentous hemagglutinin surface protein of Bordetella pertussis. A monoclonal antibody prepared against filamentous hemagglutinin (FHA) of Bordetella pertussis was found to recognize both of the high molecular weight proteins. This data suggests that the HMW and FHA proteins may serve similar biological functions. The derived amino acid sequences of the HMWl and HMW2 proteins show sequence similarity to that for the FHA protein. It has further been shown that these antigenically-related proteins are produced by the majority of the non-typeable strains of Haemophilus. Antisera raised against the protein expressed by the HMWl gene recognizes both the HMW2 protein and the B^. pertussis FHA. The present invention includes an isolated and purified high molecular weight protein of non-typeable haemophilus which is antigenically related to the B. pertussis FHA, which may be obtained from natural sources or produced recombinantly. A phage genomic library of a known strain of non-typeable Haemophilus was prepared by standard methods and the library was screened for clones expressing high molecular weight proteins, using a high titre antiserum against HMW's. A number of strongly reactive DNA clones were plaque-purified and sub-cloned into a T7 expression plasmid. It was found that they all expressed either one or the other of the two high-molecular-weight proteins designated HMWl and HMW2, with apparent molecular weights of 125 and 120 kDa, respectively, encoded by open reading frames of 4.6 kb and 4.4 kb, respectively. Representative clones expressing either HMWl or HMW2 were further characterized and the genes isolated, purified and sequenced. The DNA sequence of HMWl is shown in Figure 1 and the corresponding derived amino acid sequence in Figure 2. Similarly, the DNA sequence of HMW2 is shown in Figure 3 and the corresponding derived amino acid sequence in Figure 4. Partial purification of the isolated proteins and N-terminal sequence analysis indicated that the expressed proteins are truncated since their sequence starts at residue number 442 of both full length HMWl and HMW2 gene products. Subcloning studies with respect to the hmwl and hmw2 genes indicated that correct processing of the HMW proteins required the products of additional downstream genes. It has been found that both the hmwl and hmw2 genes are flanked by two additional downstream open reading frames (ORFs) , designated b_ and ≤, respectively, (see Figures 6 and 7) . The b ORFs are 1635 bp in length, extending from nucleotides 5114 to 6748 in the case of hmwl and nucleotides 5375 to 7009 in the case of hmw2 f with their derived amino acid sequences 99% identical. The derived amino acid sequences demonstrate similarity with the derived amino acid sequences of two genes which encode proteins required for secretion and activation of hemolysins of P. mirabilis and S. marcescens. The c ORFs are 1950 bp in length, extending from nucleotides 7062 to 9011 in the case of hmwl and nucleotides 7249 to 9198 in the case of hmw2 f with their derived amino acid sequences 96% identical. The hmwl c ORF is preceded by a series of 9 bp direct tandem repeats. In plasmid subclones, interruption of the hmwl b or £ ORF results in defective processing and secretion of the hmwl structural gene product. The two high molecular weight proteins have been isolated and purified and shown to be partially protective against otitis media in chinchillas and to function as adhesins. These results indicate the potential for use of such high molecular proteins and structurally-related proteins of other non-typeable strains of Haemophilus influenzae as components in non- typeable Haemophilus influenzae vaccines. Since the proteins provided herein are good cross-reactive antigens and are present in the majority of non-typeable Haemophilus strains, it is evident that these HMW proteins may become integral constituents of a universal Haemophilus vaccine. Indeed, these proteins may be used not only as protective antigens against otitis, sinusitis and bronchitis caused by the non-typeable Haemophilus strains, but also may be used as carriers for the protective Hib polysaccharides in a conjugate vaccine against meningitis. The proteins also may be used as carriers for other antigens, haptens and polysaccharides from other organisms, so as to induce immunity to such antigens, haptens and polysaccharides. The nucleotide sequences encoding two high molecular weight proteins of a different non-typeable Haemophilus strain (designated HMW3 and HMW4) have been largely elucidated, and are presented in Figures 8 and 9. HMW3 has an apparent molecular weight of 125 kDa while HMW4 has an apparent molecular weight of 123 kDa. These high molecular weight proteins are antigenically related to the HMWl and HMW2 proteins and to FHA. Sequence analysis of HMW3 is approximately 85% complete and of HMW4 95% complete, with short stretches at the 5'-ends of each gene remaining to be sequenced. Figure 10 contains a multiple sequence comparison of the derived amino acid sequences for the four high molecular weight proteins identified herein. As may be seen from this comparison, stretches of identical peptide sequence may be found throughout the length of the comparison, with HMW3 more closely resembling HMWl and HMW4 more closely resembling HMW2. This information is highly suggestive of a considerable sequence homology between high molecular weight proteins from various non- typeable Haemophilus strains. In addition, mutants of non-typeable H. influenzae strains that are deficient in expression of HMWl or HMW2 or both have been constructed and examined for their capacity to adhere to cultured human epithelial cells. The hmwl and hmw2 gene clusters have been expressed in E . coli and have been examined for in vitro adherence. The results of such experimentation demonstrate that both HMWl and HMW2 mediate attachment and hence are adhesins and that this function is present even in the absence of other H. influenzae surface structures. With the isolation and purification of the high molecular weight proteins, the inventors are able to determine the major protective epitopes by conventional epitope mapping and synthesize peptides corresponding to these determinants to be incorporated in fully synthetic or recombinant vaccines. Accordingly, the invention also comprises a synthetic peptide having an amino acid sequence corresponding to at least one protective epitope of a high molecular weight protein of a non-typeable Haemophilus influenzae. Such peptides are of varying length that constitute portions of the high- molecular-weight proteins, that can be used to induce immunity, either directly or as part of a conjugate, against the relative organisms and thus constitute vaccines for protection against the corresponding diseases. The present invention also provides any variant or fragment of the proteins that retains the potential immunological ability to protect against disease caused by non-typeable Haemophilus strains. The variants may be constructed by partial deletions or mutations of the genes and expression of the resulting modified genes to give the protein variations. EXAMPLES Example 1: Non-typeable H.influenzae strains 5 and 12 were isolated in pure culture from the middle ear fluid of children with acute otitis media. Chromosomal DNA from strain 12, providing genes encoding proteins HMWl and HMW2, was prepared by preparing Sau3A partial restriction digests of chromosomal DNA and fractionating on sucrose gradients. Fractions containing DNA fragments in the 9 to 20 kbp range were pooled and a library was prepared by ligation into XEMBL3 arms. Ligation mixtures were packaged in vitro and plate-amplified in a P2 lysogen of E. coli LE392. For plasmid subcloning studies, DNA from a representative recombinant phage was subcloned into the T7 expression plasmid pT7-7, containing the T7 RNA polymerase promoter ΦlO, a ribosome-binding site and the translational start site for the T7 gene 10 protein upstream from a multiple cloning site (see Figure 5B) . DNA sequence analysis was performed by the dideoxy method and both strands of the HMWl gene and a single strand of the HMW2 gene were sequenced. Western immunoblot analysis was performed to identify the recombinant proteins being produced by reactive phage clones. Phage lysates grown in LE392 cells or plaques picked directly from a lawn of LE392 cells on YT plates were solubilized in gel electrophoresis sample buffer prior to electrophoresis. Sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis was performed on 7.5% or 11% polyacrylamide modified Laem li gels. After transfer of the proteins to nitrocellulose sheets, the sheets were probed sequentially with an E. coli-absorbed human serum sample containing high-titer antibody to the high- molecular-weight proteins and then with alkaline phosphatase-conjugated goat anti-human immunoglobulin G (IgG) second antibody. Sera from healthy adults contains high-titer antibody directed against surface-exposed high-molecular-weight proteins of non-typeable Hj. influenzae. One such serum sample was used as the screening antiserum after having been extensively absorbed with LE392 cells. To identify recombinant proteins being produced by E. coli transformed with recombinant plasmids, the plasmids of interest were used to transform E. coli BL21 (DE3)/pLysS. The transformed strains were grown to an A 600 °*- °* 5 ^ n L brotn containing 50 μg of ampicillin per ml. IPTG was then added to 1 mM. One hour later, cells were harvested, and a sonicate of the cells was prepared. The protein concentrations of the samples were determined by the bicinchoninic acid method. Cell sonicates containing 100 μg of total protein were solubilized in electrophoresis sample buffer, subjected to SDS- polyacrylamide gel electrophoresis, and transferred to nitrocellulose. The nitrocellulose was then probed sequentially with the E. coli-absorbed adult serum sample and then with alkaline phosphatase-conjugated goat anti- human IgG second antibody. Western immunoblot analysis also was performed to determine whether homologous and heterologous non- typeable H. influenzae strains expressed high-molecular- weight proteins antigenically related to the protein encoded by the cloned HMWl gene (rHMWl) . Cell sonicates of bacterial cells were solubilized in electrophoresis sample buffer, subjected to SDS-polyacrylamide gel electrophoresis, and transferred to nitrocellulose. Nitrocellulose was probed sequentially with polyclonal rabbit rHMWl antiserum and then with alkaline phosphatase-conjugated goat anti-rabbit IgG second antibody. Finally, Western immunoblot analysis was performed to determine whether non-typeable Haemophilus strains expressed proteins antigenically related to the filamentous hemagglutinin protein of Bordetella pertussis. Monoclonal antibody X3C, a murine immunoglobulin G (IgG) antibody which recognizes filamentous hemagglutinin, was used to probe cell sonicates by Western blot. An alkaline phosphatase- conjugated goat anti-mouse IgG second antibody was used for detection. To generate recombinant protein antiserum, E. coli BL21(DE3)/pLysS was transformed with pHMWl-4, and expression of recombinant protein was induced with IPTG, as described above. A cell sonicate of the bacterial cells was prepared and separated into a supernatant and pellet fraction by centrifugation at 10,000 x g for 30 min. The recombinant protein fractionated with the pellet fraction. A rabbit was subcutaneously immunized on biweekly schedule with 1 mg of protein from the pellet fraction, the first dose given with Freund's complete adjuvant and subsequent doses with Freund's incomplete adjuvant. Following the fourth injection, the rabbit was bled. Prior to use in the Western blot assay, the antiserum was absorbed extensively with sonicates of the host E. coli strain transformed with cloning vector alone. To assess the sharing of antigenic determinants between HMWl and filamentous hemagglutinin, enzyme-linked immunosorbent assay (ELISA) plates (Costar, Cambridge, Mass.) were coated with 60 μl of a 4-ug/ml solution of filamentous hemagglutinin in Dulbecco's phosphate- buffered saline per well for 2 h at room temperature. Wells were blocked for 1 h with 1% bovine serum albumin in Dulbecco's phosphate-buffered saline prior to addition of serum dilutions. rHMWl antiserum was serially diluted in 0.1% Brij (Sigma, St. Louis, Mo.) in Dulbecco's phosphate-buffered saline and incubated for 3 h at room temperature. After being washed, the plates were incubated with peroxidase-conjugated goat anti-rabbit IgG antibody (Bio-Rad) for 2 h at room temperature and subse¬ quently developed with 2 , 2 '-azino-bis (3- ethylbenzthiazoline-6-sulfonic acid) (Sigma) at a concentration of 0.54 in mg/ml in 0.1 M sodium citrate buffer, pH 4.2, containing 0.03% H 2 0 2 . Absorbances were read on an automated ELISA reader. Recombinant phage expressing HMWl or HMW2 were recovered as follows. The non-typeable H. influenzae strain 12 genomic library was screened for clones expressing high-molecular-weight proteins with an E. coli-absorbed human serum sample containing a high titer of antibodies directed against the high-molecular-weight proteins. Numerous strongly reactive clones were identified along with more weakly reactive ones. Twenty strongly reactive clones were plaque-purified and examined by Western blot for expression of recombinant proteins. Each of the strongly reactive clones expressed one of two types of high-molecular-weight proteins, designated HMWl and HMW2. The major immunoreactive protein bands in the HMWl and HMW2 lysates migrated with apparent molecular masses of 125 and 120 kDa, respectively. In addition to the major bands, each lysate contained minor protein bands of higher apparent molecular weight. Protein bands seen in the HMW2 lysates at molecular masses of less than 120 kDa were not regularly observed and presumably represent proteolytic degradation products. Lysates of LE392 infected with the λEMBL3 cloning vector alone were non-reactive when immunologically screened with the same serum sample. Thus, the observed activity was not due to cross-reactive E. coli proteins or λEMBL3-encoded pro¬ teins. Furthermore, the recombinant proteins were not simply binding immunoglobulin nonspecifically, since the proteins were not reactive with the goat anti-human IgG conjugate alone, with normal rabbit sera, or with serum from a number of healthy young infants. Representative clones expressing either the HMWl or HMW2 recombinant proteins were characterized further. The restriction maps of the two phage types were different from each other, including the regions encoding the HMWl and HMW2 structural genes. Figure 5A shows restriction maps of representative recombinant phage which contained the HMWl or HMW2 structural genes. The locations of the structural genes are indicated by the shaded bars. HMWl plasmid subclones were constructed by using the T7 expression plasmid T7-7 (Fig. 5A and B) . HMW2 plasmid subclones also were constructed, and the results with these latter subclones were similar to those observed with the HMWl constructs. The approximate location and direction of transcription of the HMWl structure gene were initially determined by using plasmid pHMWl (Fig. 5A) . This plasmid was constructed by inserting the 8.5-kb BamHI- Sail fragment from λHMWl into JJamHI- and Sail-cut pT7-7. E. coli transformed with pHMWl expressed an immunoreactive recombinant protein with an apparent molecular mass of 115 kDa, which was strongly inducible with IPTG. This protein was significantly smaller than the 125-kDa major protein expressed by the parent phage, indicating that it either was being expressed as a fusion protein or was truncated at the carboxy terminus. To more precisely localize the 3' end of the structural gene, additional plasmids were constructed with progressive deletions from the 3' end of the pHMWl construct. Plasmid pHMWl-1 was constructed by digestion of pHMWl with Pstl, isolation of the resulting 8.8-kb fragment, and religation. Plasmid pHMWl-2 was constructed by digestion of pHMWl with Hindlll r isolation of the resulting 7.5-kb fragment, and religation. E. coli transformed with either plasmid pHMWl-1 or pHMWl-2 also expressed an immunoreactive recombinant protein with an apparent molecular mass of 115 kDa. These results indicated that the 3' end of the structural gene was 5' of the Hindlll site. To more precisely localize the 5' end of the gene, plasmids pHMWl-4 and pHMWl-7 were constructed. Plasmid pHMWl-4 was constructed by cloning the 5.1-kb BamHI- Hindlll fragment from λHMWl into a pT7-7-derived plasmid containing the upstream 3.8-kb EcoRI-BamHi fragment. E. coli transformed with pHMWl-4 expressed an immunoreactive protein with an apparent molecular mass of approximately 160 kDa. Although protein production was inducible with IPTG, the levels of protein production in these transformants were substantially lower than those with the pHMWl-2 transformants described above. Plasmid pHMWl-7 was constructed by digesting pHMWl-4 with Ndel and Spel. The 9.0-kbp fragment generated by this double digestion was isolated, blunt ended, and religated. E. coli transformed with pHMWl-7 also expressed an immunoreactive protein with an apparent molecular mass of 160 kDa, a protein identical in size to that expressed by the pHMWl-4 transformants. The result indicated that the initiation codon for the HMWl structural gene was 3' of the Spel site. DNA sequence analysis confirmed this conclusion. As noted above, the λHMWl phage clones expressed a major immunoreactive band of 125 kDa, whereas the HMWl plasmid clones pHMWl-4 and pHMWl-7, which contained what was believed to be the full-length gene, expressed an immunoreactive protein of approximately 160 kDa. This size discrepancy was disconcerting. One possible explanation was that an additional gene or genes necessary for correct processing of the HMWl gene product were deleted in the process of subcloning. To address this possibility, plasmid pHMWl-14 was constructed. This construct was generated by digesting pHMWl with Ndel and Mlul and inserting the 7.6-kbp Ndel-Mlul fragment isolated from pHMWl-4. Such a construct would contain the full-length HMWl gene as well as the DNA 3' of the HMWl gene which was present in the original HMWl phage. E. coli transformed with this plasmid expressed major immunoreactive proteins with apparent molecular masses of 125 and 160 kDa as well as additional degradation products. The 125- and 160-kDa bands were identical to the major and minor immunoreactive bands detected in the HMWl phage lysates. Interestingly, the pHMWl-14 construct also expressed significant amounts of protein in the uninduced condition, a situation not observed with the earlier constructs. The relationship between the 125- and 160-kDa proteins remains somewhat unclear. Sequence analysis, described below, reveals that the HMWl gene would be predicted to encode a protein of 159 kDa. It is believed that the 160-kDa protein is a precursor form of the mature 125-kDa protein, with the conversion from one protein to the other being dependent on the products of the two downstream genes. Sequence analysis of the HMWl gene (Figure 1) revealed a 4,608-bp open reading frame (ORF), beginning with an ATG codon at nucleotide 351 and ending with a TAG stop codon at nucleotide 4959. A putative ribosome- binding site with the sequence AGGAG begins 10 bp up¬ stream of the putative initiation codon. Five other in- frame ATG codons are located within 250 bp of the beginning of the ORF, but none of these is preceded by a typical ribosome-binding site. The 5'-flanking region of the ORF contains a series of direct tandem repeats, with the 7-bp sequence ATCTTTC repeated 16 times. These tandem repeats stop 100 bp 5' of the putative initiation codon. An 8-bp inverted repeat characteristic of a rho- independent transcriptional terminator is present, beginning at nucleotide 4983, 25 bp 3' of the presumed translational stop. Multiple termination codons are present in all three reading frames both upstream and downstream of the ORF. The derived amino acid sequence of the protein encoded by the HMWl gene (Figure 2) has a molecular weight of 159,000, in good agreement with the apparent molecular weights of the proteins expressed by the HMW1-4 and HMW1-7 transformants. The derived amino acid sequence of the amino terminus does not demonstrate the characteristics of a typical signal sequence. The BamHI site used in generation of pHMWl comprises bp 1743 through 1748 of the nucleotide sequence. The ORF downstream of the BamHI site would be predicted to encode a protein of 111 kDa, in good agreement with the 115 kDa estimated for the apparent molecular mass of the pHMWl- encoded fusion protein. The sequence of the HMW2 gene (Figure 3) consists of a 4,431-bp ORF, beginning with an ATG ccdon at nucleotide 352 and ending with a TAG stop codon at nucleotide 4783. The first 1,259 bp of the ORF of the HMW2 gene are identical to those of the HMWl gene. Thereafter, the sequences begin to diverge but are 80% identical overall. With the exception of a single base addition at nucleotide 93 of the HMW2 sequence, the 5'-flanking regions of the HMWl and HMW2 genes are identical for 310 bp upstream from the respective initiation codons. Thus, the HMW2 gene is preceded by the same set of tandem repeats and the same putative ribosome-binding site which lies 5' of the HMWl gene. A putative transcriptional terminator identical to that identified 3' of the HMWl ORF is noted, beginning at nucleotide 4804. The discrepancy in the lengths of the two genes is principally accounted for by a 186-bp gap in the HMW2 sequence, beginning at nucleotide position 3839. The derived amino acid sequence of the protein encoded by the HMW2 gene (Figure 4) has a molecular weight of 155,000 and is 71% identical with the derived amino acid sequence of the HMWl gene. The derived amino acid sequences of both the HMWl and HMW2 genes (Figures 2 and 4) demonstrated sequence similarity with the derived amino acid sequence of filamentous hemagglutinin of Bordetella pertussis f a surface-associated protein of this organism. The initial and optimized TFASTA scores for the HMWl-filamentous hemagglutinin sequence comparison were 87 and 186, respectively, with a word size of 2. The z score for the comparison was 45.8. The initial and optimized TFASTA scores for the HMW2-filamentous hemagglutinin sequence comparison were 68 and 196, respectively. The z score for the latter comparison was 48.7. The magnitudes of the initial and optimized TFASTA scores and the z scores suggested that a biologically significant relationship existed between the HMWl and HMW2 gene products and filamentous hemagglutinin. When the derived amino acid sequences of HMWl, HMW2, and filamentous hemagglutinin genes were aligned and compared, the similarities were most notable at the amino-terminal ends of the three sequences. Twelve of the first 22 amino acids in the predicted peptide sequences were identical. In additional, the sequences demonstrated a common five- amino-acid stretch, Asn-Pro-Asn-Gly-Ile, and several shorter stretches of sequence identity within the first 200 amino acids. Example 2: To further explore the HMWl-filamentous hemagglutinin relationship, the ability of antiserum prepared against the HMW1-4 recombinant protein (rHMWl) to recognize purified filamentous hemagglutinin was assessed. The rHMWl antiserum demonstrated ELISA reactivity with filamentous hemagglutinin in a dose- dependent manner. Preimmune rabbit serum had minimal reactivity in this assay. The rHMWl antiserum also was examined in a Western blot assay and demonstrated weak but positive reactivity with purified filamentous hemagglutinin in this system also. To identify the native Haemophilus protein corresponding to the HMWl gene product and to determine the extent to which proteins antigenically related to the HMWl cloned gene product were common among other non- typeable H. influenzae strains, a panel of Haemophilus strains was screened by Western blot with the rHMWl antiserum. The antiserum recognized both a 125- and a 120-kDa protein band in the homologous strain 12, the putative mature protein products of the HMWl and HMW2 genes, respectively. When used to screen heterologous non-typeable H. influenzae strains, rHMWl antiserum recognized high- molecular-weight proteins in 75% of 125 epidemiologically unrelated strains. In general, the antiserum reacted with one or two protein bands in the 100- to 150-kDa range in each of the heterologous strains in a pattern similar but not identical to that seen in the homologous strain. Monoclonal antibody X3C is a murine IgG antibody directed against the filamentous hemagglutinin protein of B. pertussis. This antibody can inhibit the binding of B. pertussis cells to Chinese hamster ovary cells and HeLa cells in culture and will inhibit hemagglutination of erythrocytes by purified filamentous hemagglutinin. A Western blot assay was performed in which this monoclonal antibody was screened against the same panel of non-typeable H. influenzae strains discussed above. Monoclonal antibody X3C recognized both the high- molecular-weight proteins in non-typeable H. influenzae strain 12 which were recognized by the recombinant- protein antiserum. In addition, the monoclonal antibody recognized protein bands in a subset of heterologous non- typeable H. influenzae strains which were identical to those recognized by the recombinant-protein antiserum. On occasion, the filamentous hemagglutinin monoclonal antibody appeared to recognize only one of the two bands which had been recognized by the recombinant-protein antiserum. Overall, monoclonal antibody X3C recognized high-molecular-weight protein bands identical to those recognized by the rHMWl antiserum in approximately 35% of our collection of non-typeable H. influenzae strains. Example 3: Mutants deficient in expression of HMWl, MW2 or both proteins were constructed to examine the role of these proteins in bacterial adherence. The following strategy was employed. pHMWl-14 (see Example 1, Figure 5A) was digested with BamHI and then ligated to a kanamycin cassette isolated on a 1.3-kb BamHI fragment from pUC4K. The resultant plasmid (pHMWl-17) was linearized by digestion with Xbal and transformed into non-typeable J . influenzae strain 12, followed by selection for kanamycin resistant colonies. Southern analysis of a series of these colonies demonstrated two populations of transformants, one with an insertion in the HMWl structural gene and the other with an insertion in the HMW2 structural gene. One mutant from each of these classes was selected for further studies. Mutants deficient in expression of both proteins were recovered using the following protocol. After deletion of the 2.1-kb fragment of DNA between two EcoRI sites spanning the 3'-portion of the HMWl structural gene in pHMW-15, the kanamycin cassette from pUC4K was inserted as a 1.3-kb EcoRI fragment. The resulting plasmid (pHMWl-16) waε linearized by digestion with Xbal and transformed into strain 12, followed again by selection for kanamycin resistant colonies. Southern analysis of a representative sampling of these colonies demonstrated that in seven of eight caseε, insertion into both the HMWl and HMW2 loci had occurred. One such mutant was selected for further studies. To confirm the intended phenotypes, the mutant strains were examined by Western blot analysis with a polyclonal antiserum against recombinant HMWl protein. The parental strain expressed both the 125-kD HMWl and the 120-kD HMW2 protein. In contraεt, the HMW2" mutant failed to express the 120-kD protein, and the HMWl mutant failed to express the 125-kD protein. The double mutant lacked expression of either protein. On the baεiε of whole cell lysates, outer membrane profiles, and colony morphology, the wild type strain and the mutants were otherwise identical with one another. Transmisεion electron microscopy demonstrated that none of the four strains expresεed pili. The capacity of wild type strain 12 to adhere to Chang epithelial cells was examined. In such assays, bacteria were inoculated into broth and allowed to grow to a density of ~2 x IO 9 cfu/ l. Approximately 2 x IO 7 cfu were inoculated onto epithelial cell monolayerε, and plates were gently centrifuged at 165 x g for 5 minutes to facilitate contact between bacteria and the epithelial εurface. After incubation for 30 minutes at 37*C in 5% C0 2 , monolayers were rinεed 5 times with PBS to remove nonadherent organisms and were treated with trypsin-EDTA (0.05% trypsin, 0.5% EDTA) in PBS to release them from the plastic εupport. Well contentε were agitated, and dilutions were plated on solid medium to yield the number of adherent bacteria per monolayer. Percent adherence was calculated by dividing the number of adherent cfu per monolayer by the number of inoculated cfu. As depicted in Table 1 below (the Tables appear at the end of the descriptive text) , this strain adhered quite efficiently, with nearly 90% of the inoculum binding to the monolayer. Adherence by the mutant expressing HMWl but not HMW2 (HMW2 " ) was also quite efficient and comparable to that by the wild type strain. In contrast, attachment by the strain expressing HMW2 but deficient in expression of HMWl (HMWl * ) waε decreased about 15-fold relative to the wild type. Adherence by the double mutant (HMW1'/HMW2 ~ ) was decreased even further, approximately 50-fold compared with the wild type and approximately 3-fold compared with the HMWl mutant. Considered together, these resultε suggest that both the HMWl protein and the, HMW2 protein influence attachment to Chang epithelial cells. Interestingly, optimal adherence to this cell line appears to require HMWl but not HMW2. Example 4 : Using the plasmidε pHMWl-16 and pHMWl-17 (εee Example 3) and following a scheme similar to that employed with strain 12 as described in Example 3, three non-typeable Haemophilus strain 5 mutants were isolated, including one with the kanamycin gene inserted into the hmwl-like (designated hmw3ϊ locuε, a εecond with an insertion in the hmw2-like (designated hmw4. locus, and a third with insertions in both loci. As predicted, Western immunoblot analysis demonstrated that the mutant with insertion of the kanamycin cassette into the hmwl- like locus had lost expression of the HMW3 125-kD protein, while the mutant with insertion into the hmw2- like locus failed to expresε the HMW4 123-kD protein. The mutant with a double insertion was unable to expresε either of the high molecular weight proteinε. As shown in Table 1 below, wild type εtrain 5 demonstrated high level adherence, with almost 80% of the inoculum adhering per monolayer. Adherence by the mutant deficient in expression of the HMW2-like protein was also quite high. In contrast, adherence by the mutant unable to express the, HMWl-like protein was reduced about 5- fold relative to the wild type, and attachment by the double mutant was diminished even further (approximately 25-fold) . Examination of Giemsa-εtained samples confirmed these observations (not shown) . Thus, the results with εtrain 5 corroborate the findings with strain 12 and the HMWl and HMW2 proteins. Example 5: To confirm an adherence function for the HMWl and HMW2 proteins and to examine the effect of HMWl and HMW2 independently of other H. influenzae surface structures, the hmwl and the hmw2 gene clusters were introduced into E. coli DH5α, using plasmidε pHMWl-14 and pHMW2-21, reεpectively. Aε a control, the cloning vector, pT7-7, waε alεo transformed into E. coli DH5 . Western blot analysis demonεtrated that E. coli DH5α containing the hmwl geneε expressed a 125 kDa protein, while the same strain harboring the hmw2 genes expreεεed a 120-kDa protein. E. coli DH5 containing pT7-7 failed to react with antiserum against recombinant HMWl. Transmission electron microscopy revealed no pili or other surface appendages on any of the E. coli strains. Adherence by the E. coli strains was quantitated and compared with adherence by wild type non-typeable IL. influenzae strain 12. As shown in Table 2 below, adherence by E. coli DH5α containing vector alone was lesε than 1% of that for strain 12. In contrast, E. coli DH5α harboring the hmwl gene cluεter demonεtrated adherence levels comparable to those for strain 12. Adherence by E. coli DH5α containing the hmw2 genes was approximately 6-fold lower than attachment by strain 12 but was increased 20-fold over adherence by E. coli DH5α with pT7-7 alone. Theεe results indicate that the HMWl and HMW2 proteins are capable of independently mediating attachment to Chang conjunctival cells. These results are consiεtent with the results with the H. influenzae mutants reported in Exampleε 3 and 4, providing further evidence that, with Chang epithelial cells, HMWl iε a more efficient adheεin than is HMW2. Experimentε with E. coli HB101 harboring pT7-7, pHMWl-14, or pHMW2-21 confirmed the results obtained with the DH5α derivatives (see Table 2) . Example 6: HMWl and HMW2 were isolated and purified from non- typeable H. influenzae (NTHI) εtrain 12 in the following manner. Non-typeable Haemophiluε bacteria from frozen stock culture were streaked onto a chocolate plate and grown overnight at 37*C in an incubator with 5% C0 2 . 50ml starter culture of brain heart infusion (BHI) broth, supplemented with 10 μg/ml each of hemin and NAD was inoculated with growth on chocolate plate. The starter culture was grown until the optical denεity (O.D. - 600nm) reached 0.6 to 0.8 and then the bacteria in the εtarter culture waε used to inoculate six 500 ml flasks of supplemented BHI using 8 to 10 ml per flask. The bacteria were grown in 500 ml flasks for an additional 5 to 6 hours at which time the O.D. was 1.5 or greater. Cultures were centrifuged at 10,000 rpm for 10 minutes. Bacterial pellets were resuspended in a total volume of 250 ml of an extraction solution comprising 0.5 M NaCl, 0.01 M Na 2 EDTA, 0.01 M Tris 50 μM 1,10- phenanthroline, pH 7.5. The cells were not sonicated or otherwise disrupted. The resuspended cells were allowed to sit on ice at 0*C for 60 minutes. The resuspended cells were centrifuged at 10,000 rpm for 10 minutes at 4'C to remove the majority of intact cells and cellular debris. The supernatant was collected and centrifuged at 100,000 xg for 60 minuteε at 4*C. The supernatant again waε collected and dialyzed overnight at 4°C against 0.01 M sodium phosphate, pH 6.0. The sample was centrifuged at 10,000 rpm for 10 minutes at 4*C to remove insoluble debris precipitated from solution during dialysis. The supernatant waε applied to a 10 ml CM Sepharose column which haε been pre-equilibrated with 0.01 M sodium phosphate, pH 6. Following application to this column, the column was washed with 0.01 M sodium phosphate. Proteins were elevated from the column with a 0 - 0.5M KC1 gradient in 0.01 M Na phosphate, pH 6 and fractions were collected for gel examination. Coomasεie gels of column fractions were carried out to identify those fractions containing high molecular weight proteins. The fractions containing high molecular weight proteins were pooled and concentrated to a 1 to 3 ml volume in preparation for application of sample to gel filtration column. A Sepharose CL-4B gel filtration column was equilibrated with phosphate-buffered saline, pH 7.5. The concentrated high molecular weight protein sample was applied to the gel filtration column and column fractions were collected. Coomassie gelε were performed on the column fractions to identify those containing high molecular weight proteins. The column fractions containing high molecular weight proteins were pooled. The proteinε were tested to determine whether they would protect against experimental otitis media caused by the homologous strain. Chinchillas received three monthly subcutaneous injections with 40 μg of an HMW1-HMW2 protein mixture in Freund's adjuvant. One month after the last injection, the animals were challenged by intrabullar inoculation with 300 cfu of NTHI strain 12. Infection developed in 5 of 5 control animals versus 5 of 10 immunized animals. Among infected animals, geometric mean bacterial counts in middle ear fluid 7 days post-challenge were 7.4 x IO 6 in control animals verus 1.3 x 10 s in immunized animals. Serum antibody titres following immunization were comparable in uninfected and infected animals. However, infection in immunized animals was uniformly associated with the appearance of bacteria down-regulated in expression of the HMW proteinε, suggesting bacterial selection in response to immunologic pressure. Although this data shows that protection following immunization was not complete, this data suggests the HMW adhesin proteins are potentially important protective antigens which may comprise one component of a ulti- component NTHI vaccine. These animal challenge testε wererepeated in Chinchillas at a lower dose challenge than the 300 cfu employed above. In this instance, complete protection waε achieved. In these experiments, groups of five animalε were immunized with 20 μg of the HMW1-HMW2 mixture on dayε 1, 28, and 42 in the preεence of A1P0 A . Blood samples were collected on day 53 to monitor the antibody response. On day 56, the left ear of animals was challenged with about 10 cfu of H. influenzae strain 12. Ear infection was monitored on day 4. Four animals in Group 3 were infected previously by H. influenzae strain 12 and were recovered completely for at least one month before the second challenge. The resultε are outlined in the following Table A: TABLE A Protective ability of HMW protein against non-typeable H. influenzae challenge in chinchilla model Group Antigens Total Number of Animals Showed Animals Positive Ear Infection (#) Tympano- Otosco- cfu of gram pic Bac¬ Examin¬ teria/ ation 10 μL 1 HMW 5 0 0 0 2 None 5 5 5 850- 3200 (4/5) 3 Convalescent 4 0 0 0 Example 7: A number of synthetic peptides were derived from HMWl. Antiεera then waε raiεed to these peptides. The anti-peptide antisera to peptide HMW1-P5 was shown to recognize HMWl. Peptide HMW1-P5 covers amino acids 1453 to 1481 of HMWl, has the sequence VDEVIEAKRILEKVKDLSDEEREALAKLG (SEQ ID NO:9), and represents baseε 1498 to 1576 in Figure 10. Thiε finding demonstrates that the DNA sequence and the derived protein is being interpreted in the correct reading frame and that peptideε derived from the εequence can be produced which will be immunogenic. SUMMARY OF DISCLOSURE In εummary of this disclosure, the preεent invention provideε high molecular weight proteinε of non-typeable Haemophiluε. geneε coding for the same and vaccineε incorporating εuch proteinε. Modifications are possible within the scope of this invention. Table I. Effect of mutation of high molecular weight proteins on adherence to Chang epithelial cells by nontypa bl e H. influenzae. ADHERENCE * S tra i n "5 inoculum relatJYC to wjjd type* Strain 12 derivatives wild type 87.7 ± 5.9 100.0 ± 6.7 HMWl- mutant 6.0 ± 0.9 6.8 ± 1.0 HMW2- mutant 89.9 + 10.8 102.5 ± 12.3 HMW1-/HMW2- mutant 2.0 ± 0.3 2.3 ± 0.3 Strain 5 derivatives wild type 78.7 + 3.2 100.0 + 4.1 HMWl -like mutant 15.7 ± 2.6 19.9 + 3.3 HMW2-like mutant 103.7 + 14.0 131.7 + 17.8 double mutant 3.5 + 0.6 4.4 + 0.8 * Numbers represent mean (+. standard error of the mean) of measurements in triplicate or quadruplicate from representative experiments. " Adherence values for strain 12 derivatives are relative to strain 12 wild type; values for strain 5 derivatives are relative to strain 5 wild type. Table 2. Adherence by E. coli DH5α and HB101 harboring hmwl or h m wl gene clusters. Adherence relative to Strain * TJ. infl pnrap strain 12t DH5α (pT7-7) 0.7 ± 0.02 DH5α (pHMWl-i4) 114.2 ± 15.9 DH5α (pHMW2-21) 14.0 ± 3.7 HB101 (pT7-7) 1.2 ± 0.5 HB101 (pHMWl-14) 93.6 ± 15.8 HB101 (pHMW2-21) 3.6 ± 0.9 The plasmid pHMWl-14 contains the hmwl gene cluster, while pHMW2-21 contains the hmwl gene cluster; pT7-7 is the cloning vector used in these constructs. Numbers represent the mean (+ standard error of the mean) of measurements made in triplicate from representative experiments. SEQUENCE LISTING (1) GENERAL INFORMATION: (i) APPLICANT: BARENKAMP, STEPHEN J ST. GEME III, JOSEPH W (ii) TITLE OF INVENTION: HIGH MOLECULAR WEIGHT SURFACE PROTEINS OF NON-TYPEABLE HAEMOPHILUS (iii) NUMBER OF SEQUENCES: 8 (iv) CORRESPONDENCE ADDRESS: (A) ADDRESSEE: Shoemaker and Mattare, Ltd (B) STREET: 2001 Jefferson Davis H y. , 1203 Crystal Plaza Bldg. 1 (C) CITY: Arlington (D) STATE: Virginia (E) COUNTRY: U.S.A. (F) ZIP: 22202-0286 (v) COMPUTER READABLE FORM: (A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS (D) SOFTWARE: Patentln Release #1.0, Version #1.25 (vi) CURRENT APPLICATION DATA: (A) APPLICATION NUMBER: US 08/038,682 (B) FILING DATE: 16-MAR-1993 (C) CLASSIFICATION: (viii) ATTORNEY/AGENT INFORMATION: (A) NAME: BERKSTRESSER, JERRY W (B) REGISTRATION NUMBER: 22,651 (C) REFERENCE/DOCKET NUMBER: 1038-293 (ix) TELECOMMUNICATION INFORMATION: (A) TELEPHONE: (703) 415-0810 (B) TELEFAX: (703) 415-0813 (2) INFORMATION FOR SEQ ID NO:l: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5116 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1: ACAGCGTTCT CTTAATACTA GTACAAACCC ACAATAAAAT ATGACAAACA ACAATTACAA 60 CACCTTTTTT GCAGTCTATA TGCAAATATT TTAAAAAATA GTATAAATCC GCCATATAAA 120 ATGGTATAAT CTTTCATCTT TCATCTTTCA TCTTTCATCT TTCATCTTTC ATCTTTCATC 180 TTTCATCTTT CATCTTTCAT CTTTCATCTT TCATCTTTCA TCTTTCATCT TTCATCTTTC 240 ACATGCCCTG ATGAACCGAG GGAAGGGAGG GAGGGGCAAG AATGAAGAGG GAGCTGAACG 300 ^ • jnCTϊTUTΕ SHEET (RULE 26) AACGCAAATG ATAAAGTAAT TTAATTGTTC AACTAACCTT AGGAGAAAAT ATGAACAAGC 360 TATATCGTCT CAAATTCAGC AAACGCCTGA ATGCTTTGGT TGCTGTGTCT GAATTGGCAC 420 GGGGTTGTGA CCATTCCACA GAAAAAGGCA GCGAAAAACC TGCTCGCATG AAAGTGCGTC 480 ACTTAGCGTT AAAGCCACTT TCCGCTATGT TACTATCTTT AGGTGTAACA TCTATTCCAC 540 AATCTGTTTT AGCAAGCGGC TTACAAGGAA TGGATGTAGT ACACGGCACA GCCACTATGC 600 AAGTAGATGG TAATAAAACC ATTATCCGCA ACAGTGTTGA CGATATCATT AATTGGAAAC 660 AATTTAACAT CGACCAAAAT GAAATGGTGC AGTTTTTACA AGAAAACAAC AACTCCGCCG 720 TATTCAACCG TGTTACATCT AACCAAATCT CCCAATTAAA AGGGATTTTA GATTCTAACG 780 GACAAGTCTT TTTAATCAAC CCAAATGGTA TCACAATAGG TAAAGACGCA ATTATTAACA 840 CTAATGGCTT TACGGCTTCT ACGCTAGACA TTTCTAACGA AAACATCAAG GCGCGTAATT 900 TCACCTTCGA GCAAACCAAA GATAAAGCGC TCGCTGAAAT TGTGAATCAC GGTTTAATTA 960 CTGTCGGTAA AGACGGCAGT GTAAATCTTA TTGGTGGCAA AGTGAAAAAC GAGGGTGTGA 1020 TTAGCGTAAA TGGTGGCAGC ATTTCTTTAC TCGCAGGGCA AAAAATCACC ATCAGCGATA 1080 TAATAAACCC AACCATTACT TACAGCATTG CCGCGCCTGA AAATGAAGCG GTCAATCTGG 1140 GCGATATTTT TGCCAAAGGC GGTAACATTA ATGTCCGTGC TGCCACTATT CGAAACCAAG 1200 GTAAACTTTC TGCTGATTCT GTAAGCAAAG ATAAAAGCGG CAATATTGTT CTTTCCGCCA 1260 AAGAGGGTGA AGCGGAAATT GGCGGTGTAA TTTCCGCTCA AAATCAGCAA GCTAAAGGCG 1320 GCAAGCTGAT GATTACAGGC GATAAAGTCA CATTAAAAAC AGGTGCAGTT ATCGACCTTT 1380 CAGGTAAAGA AGGGGGAGAA ACTTACCTTG GCGGTGACGA GCGCGGCGAA GGTAAAAAGG 1440 GCATTCAATT AGCAAAGAAA ACCTCTTTAG AAAAAGGCTC AACCATCAAT GTATCAGGCA 1500 AAGAAAAAGG CGGACGCGCT ATTGTGTGGG GCGATATTGC GTTAATTGAC GGCAATATTA 1560 ACGCTCAAGG TAGTGGTGAT ATCGCTAAAA CCGGTGGTTT TGTGGAGACG TCGGGGCATG 16 0 ATTTATTCAT CAAAGACAAT GCAATTGTTG ACGCCAAAGA GTGGTTGTTA GACCCGGATA 1680 ATGTATCTAT TAATGCAGAA ACAGCAGGAC GCAGCAATAC TTCAGAAGAC GATGAATACA 1740 CGGGATCCGG GAATAGTGCC AGCACCCCAA AACGAAACAA AGAAAAGACA ACATTAACAA 1800 ACACAACTCT TGAGAGTATA CTAAAAAAAG GTACCTTTGT TAACATCACT GCTAATCAAC 1860 GCATCTATGT CAATAGCTCC ATTAATTTAT CCAATGGCAG CTTAACTCTT TGGAGTGAGG 1920 GTCGGAGCGG TGGCGGCGTT GAGATTAACA ACGATATTAC CACCGGTGAT GATACCAGAG 1980 GTGCAAACTT AACAATTTAC TCAGGCGGCT GGGTTGATGT TCATAAAAAT ATCTCACTCG 2040 GGGCGCAAGG TAACATAAAC ATTACAGCTA AACAAGATAT CGCCTTTGAG AAAGGAAGCA 2100 ACCAAGTCAT TACAGGTCAA GGGACTATTA CCTCAGGCAA TCAAAAAGGT TTTAGATTTA 2160 ATAATGTCTC TCTAAACGGC ACTGGCAGCG GACTGCAATT CACCACTAAA AGAACCAATA 2220 AATACGCTAT CACAAATAAA TTTGAAGGGA CTTTAAATAT TTCAGGGAAA GTGAACATCT 2280 CAATGGTTTT ACCTAAAAAT GAAAGTGGAT ATGATAAATT CAAAGGACGC ACTTACTGGA 23 0 SUBSTITϋ It SHEET (RULE 26) ATTTAACCTC CTTAAATGTT TCCGAGAGTG GCGAGTTTAA CCTCACTATT GACTCCAGAG 2400 GAAGCGATAG TGCAGGCACA CTTACCCAGC CTTATAATTT AAACGGTATA TCATTCAACA 2460 AAGACACTAC CTTTAATGTT GAACGAAATG CAAGAGTCAA CTTTGACATC AAGGCACCAA 2520 TAGGGATAAA TAAGTATTCT AGTTTGAATT ACGCATCATT TAATGGAAAC ATTTCAGTTT 2580 CGGGAGGGGG GAGTGTTGAT TTCACACTTC TCGCCTCATC CTCTAACGTC CAAACCCCCG 2640 GTGTAGTTAT AAATTCTAAA TACTTTAATG TTTCAACAGG GTCAAGTTTA AGATTTAAAA 2700 CTTCAGGCTC AACAAAAACT GGCTTCTCAA TAGAGAAAGA TTTAACTTTA AATGCCACCG 2760 GAGGCAACAT AACACTTTTG CAAGTTGAAG GCACCGATGG AATGATTGGT AAAGGCATTG 2820 TAGCCAAAAA AAACATAACC TTTGAAGGAG GTAACATCAC CTTTGGCTCC AGGAAAGCCG 2880 TAACAGAAAT CGAAGGCAAT GTTACTATCA ATAACAACGC TAACGTCACT CTTATCGGTT 2940 CGGATTTTGA CAACCATCAA AAACCTTTAA CTATTAAAAA AGATGTCATC ATTAATAGCG 3000 GCAACCTTAC CGCTGGAGGC AATATTGTCA ATATAGCCGG AAATCTTACC GTTGAAAGTA 3060 ACGCTAATTT CAAAGCTATC ACAAATTTCA CTTTTAATGT AGGCGGCTTG TTTGACAACA 3120 AAGGCAATTC AAATATTTCC ATTGCCAAAG GAGGGGCTCG CTTTAAAGAC ATTGATAATT 3180 CCAAGAATTT AAGCATCACC ACCAACTCCA GCTCCACTTA CCGCACTATT ATAAGCGGCA 3240 ATATAACCAA TAAAAACGGT GATTTAAATA TTACGAACGA AGGTAGTGAT ACTGAAATGC 3300 AAATTGGCGG CGATGTCTCG CAAAAAGAAG GTAATCTCAC GATTTCTTCT GACAAAATCA 3360 ATATTACCAA ACAGATAACA ATCAAGGCAG GTGTTGATGG GGAGAATTCC GATTCAGACG 3420 CGACAAACAA TGCCAATCTA ACCATTAAAA CCAAAGAATT GAAATTAACG CAAGACCTAA 3480 ATATTTCAGG TTTCAATAAA GCAGAGATTA CAGCTAAAGA TGGTAGTGAT TTAACTATTG 3540 GTAACACCAA TAGTGCTGAT GGTACTAATG CCAAAAAAGT AACCTTTAAC CAGGTTAAAG 3600 ATTCAAAAAT CTCTGCTGAC GGTCACAAGG TGACACTACA CAGCAAAGTG GAAACATCCG 3660 GTAGTAATAA CAACACTGAA GATAGCAGTG ACAATAATGC CGGCTTAACT ATCGATGCAA 3720 AAAATGTAAC AGTAAACAAC AATATTACTT CTCACAAAGC AGTGAGCATC TCTGCGACAA 3780 GTGGAGAAAT TACCACTAAA ACAGGTACAA CCATTAACGC AACCACTGGT AACGTGGAGA 3840 TAACCGCTCA AACAGGTAGT ATCCTAGGTG GAATTGAGTC CAGCTCTGGC TCTGTAACAC 3900 TTACTGCAAC CGAGGGCGCT CTTGCTGTAA GCAATATTTC GGGCAACACC GTTACTGTTA 3960 CTGCAAATAG CGGTGCATTA ACCACTTTGG CAGGCTCTAC AATTAAAGGA ACCGAGAGTG 4020 TAACCACTTC AAGTCAATCA GGCGATATCG GCGGTACGAT TTCTGGTGGC ACAGTAGAGG 4080 TTAAAGCAAC CGAAAGTTTA ACCACTCAAT CCAATTCAAA AATTAAAGCA ACAACAGGCG 4140 AGGCTAACGT AACAAGTGCA ACAGGTACAA TTGGTGGTAC GATTTCCGGT AATACGGTAA 4200 ATGTTACGGC AAACGCTGGC GATTTAACAG TTGGGAATGG CGCAGAAATT AATGCGACAG 4260 AAGGAGCTGC AACCTTAACT ACATCATCGG GCAAATTAAC TACCGAAGCT AGTTCACACA 4320 TTACTTCAGC CAAGGGTCAG GTAAATCTTT CAGCTCAGGA TGGTAGCGTT GCAGGAAGTA 4380 r r— r ?mUTE SHEET (RULE 26) TTAATGCCGC CAATGTGACA CTAAATACTA CAGGCACTTT AACTACCGTG AAGGGTTCAA 4440 ACATTAATGC AACCAGCGGT ACCTTGGTTA TTAACGCAAA AGACGCTGAG CTAAATGGCG 4500 CAGCATTGGG TAACCACACA GTGGTAAATG CAACCAACGC AAATGGCTCC GGCAGCGTAA 4560 TCGCGACAAC CTCAAGCAGA GTGAACATCA CTGGGGATTT AATCACAATA AATGGATTAA 4620 ATATCATTTC AAAAAACGGT ATAAACACCG TACTGTTAAA AGGCGTTAAA ATTGATGTGA 4680 AATACATTCA ACCGGGTATA GCAAGCGTAG ATGAAGTAAT TGAAGCGAAA CGCATCCTTG 4740 AGAAGGTAAA AGATTTATCT GATGAAGAAA GAGAAGCGTT AGCTAAACTT GGAGTAAGTG 4800 CTGTACGTTT TATTGAGCCA AATAATACAA TTACAGTCGA TACACAAAAT GAATTTGCAA 4860 CCAGACCATT AAGTCGAATA GTGATTTCTG AAGGCAGGGC GTGTTTCTCA AACAGTGATG 4920 GCGCGACGGT GTGCGTTAAT ATCGCTGATA ACGGGCGGTA GCGGTCAGTA ATTGACAAGG 4980 TAGATTTCAT CCTGCAATGA AGTCATTTTA TTTTCGTATT ATTTACTGTG TGGGTTAAAG 5040 TTCAGTACGG GCTTTACCCA TCTTGTAAAA AATTACGGAG AATACAATAA AGTATTTTTA 5100 ACAGGTTATT ATTATG 5116 (2) INFORMATION FOR SEQ ID NO:2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1536 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: Met Asn Lys lie Tyr Arg Leu Lys Phe Ser Lys Arg Leu Asn Ala Leu 1 5 10 15 Val Ala Val Ser Glu Leu Ala Arg Gly Cys Asp His Ser Thr Glu Lys 20 25 30 Gly Ser Glu Lys Pro Ala Arg Met Lys Val Arg His Leu Ala Leu Lys 35 40 45 Pro Leu Ser Ala Met Leu Leu Ser Leu Gly Val Thr Ser lie Pro Gin 50 55 60 Ser Val Leu Ala Ser Gly Leu Gin Gly Met Asp Val Val His Gly Thr 65 70 75 80 Ala Thr Met Gin Val Asp Gly Asn Lys Thr lie lie Arg Asn Ser Val 85 90 95 Asp Ala lie lie Asn Trp Lys Gin Phe Asn lie Asp Gin Asn Glu Met 100 105 110 Val Gin Phe Leu Gin Glu Asn Asn Asn Ser Ala Val Phe Asn Arg Val 115 120 125 Thr Ser Asn Gin lie Ser Gin Leu Lys Gly lie Leu Asp Ser Asn Gly 130 135 140 Gin Val Phe Leu lie Asn Pro Asn Gly lie Thr lie Gly Lys Asp Ala 145 150 155 160 lie lie Asn Thr Asn Gly Phe Thr Ala Ser Thr Leu Asp lie Ser Asn 165 170 175 Glu Asn lie Lys Ala Arg Asn Phe Thr Phe Glu Gin Thr Lys Asp Lys 180 185 190 Ala Leu Ala Glu lie Val Asn His Gly Leu lie Thr Val Gly Lys Asp 195 200 205 Gly Ser Val Asn Leu lie Gly Gly Lys Val Lys Asn Glu Gly Val lie 210 215 220 Ser Val Asn Gly Gly Ser lie Ser Leu Leu Ala Gly Gin Lys lie Thr 225 230 235 240 lie Ser Asp lie lie Asn Pro Thr lie Thr Tyr Ser lie Ala Ala Pro 245 250 255 Glu Asn Glu Ala Val Asn Leu Gly Asp lie Phe Ala Lys Gly Gly Asn 260 265 270 lie Asn Val Arg Ala Ala Thr lie Arg Asn Gin Gly Lys Leu Ser Ala 275 280 285 Asp Ser Val Ser Lys Asp Lys Ser Gly Asn lie Val Leu Ser Ala Lys 290 295 300 Glu Gly Glu Ala Glu He Gly Gly Val He Ser Ala Gin Asn Gin Gin 305 310 315 320 Ala Lys Gly Gly Lys Leu Met He Thr Gly Asp Lys Val Thr Leu Lys 325 330 335 Thr Gly Ala Val He Asp Leu Ser Gly Lys Glu Gly Gly Glu Thr Tyr 340 345 350 Leu Gly Gly Asp Glu Arg Gly Glu Gly Lys Asn Gly He Gin Leu Ala 355 360 365 Lys Lys Thr Ser Leu Glu Lys Gly Ser Thr He Asn Val Ser Gly Lys 370 375 380 Glu Lys Gly Gly Arg Ala He Val Trp Gly Asp He Ala Leu He Asp 385 390 395 400 Gly Asn He Asn Ala Gin Gly Ser Gly Asp He Ala Lys Thr Gly Gly 405 410 415 Phe Val Glu Thr Ser Gly His Asp Leu Phe He Lys Asp Asn Ala He 420 425 430 Val Asp Ala Lys Glu Trp Leu Leu Asp Phe Asp Asn Val Ser He Asn 435 440 445 Ala Glu Thr Ala Gly Arg Ser Asn Thr Ser Glu Asp Asp Glu Tyr Thr 450 455 460 Gly Ser Gly Asn Ser Ala Ser Thr Pro Lys Arg Asn Lys Glu Lys Thr 465 470 475 480 Thr Leu Thr Asn Thr Thr Leu Glu Ser He Leu Lys Lys Gly Thr Phe 485 490 495 Val Asn He Thr Ala Asn Gin Arg He Tyr Val Asn Ser Ser He Asn 500 505 510 Leu Ser Asn Gly Ser Leu Thr Leu Trp Ser Glu Gly Arg Ser Gly Gly 515 520 525 Gly Val Glu He Asn Asn Asp He Thr Thr Gly Asp Asp Thr Arg Gly 530 535 540 Ala Asn Leu Thr He Tyr Ser Gly Gly Trp Val Asp Val His Lys Asn 545 550 555 560 He Ser Leu Gly Ala Gin Gly Asn He Asn He Thr Ala Lys Gin Asp 565 570 575 He Ala Phe Glu Lys Gly Ser Asn Gin Val He Thr Gly Gin Gly Thr 580 585 590 He Thr Ser Gly Asn Gin Lys Gly Phe Arg Phe Asn Asn Val Ser Leu 595 600 605 Asn Gly Thr Gly Ser Gly Leu Gin Phe Thr Thr Lys Arg Thr Asn Lys 610 615 620 Tyr Ala He Thr Asn Lys Phe Glu Gly Thr Leu Asn He Ser Gly Lys 625 630 635 640 Val Asn He Ser Met Val Leu Pro Lys Asn Glu Ser Gly Tyr Asp Lys 645 650 655 Phe Lys Gly Arg Thr Tyr Trp Asn Leu Thr Ser Leu Asn Val Ser Glu 660 665 670 Ser Gly Glu Phe Asn Leu Thr He Asp Ser Arg Gly Ser Asp Ser Ala 675 680 685 Gly Thr Leu Thr Gin Pro Tyr Asn Leu Asn Gly He Ser Phe Asn Lys 690 695 700 Asp Thr Thr Phe Asn Val Glu Arg Asn Ala Arg Val Asn Phe Asp He 705 710 715 720 Lys Ala Pro He Gly He Asn Lys Tyr Ser Ser Leu Asn Tyr Ala Ser 725 730 735 Phe Asn Gly Asn He Ser Val Ser Gly Gly Gly Ser Val Asp Phe Thr 740 745 750 Leu Leu Ala Ser Ser Ser Asn Val Gin Thr Pro Gly Val Val He Asn 755 760 765 Ser Lys Tyr Phe Asn Val Ser Thr Gly Ser Ser Leu Arg Phe Lys Thr 770 775 780 Ser Gly Ser Thr Lys Thr Gly Phe Ser He Glu Lys Asp Leu Thr Leu 785 790 795 800 Asn Ala Thr Gly Gly Asn He Thr Leu Leu Gin Val Glu Gly Thr Asp 805 810 815 Gly Met He Gly Lys Gly He Val Ala Lys Lys Asn He Thr Phe Glu 820 825 830 Gly Gly Asn He Thr Phe Gly Ser Arg Lys Ala Val Thr Glu He Glu 835 840 845 Gly Asn Val Thr He Asn Asn Asn Ala Asn Val Thr Leu He Gly Ser 850 855 860 Asp Phe Asp Asn His Gin Lys Pro Leu Thr He Lys Lys Asp Val He 865 870 875 880 He Asn Ser Gly Asn Leu Thr Ala Gly Gly Asn He Val Asn He Ala 885 890 895 Gly Asn Leu Thr Val Glu Ser Asn Ala Asn Phe Lys Ala He Thr Asn 900 905 910 Phe Thr Phe Asn Val Gly Gly Leu Phe Asp Asn Lys Gly Asn Ser Asn 915 920 925 He Ser He Ala Lys Gly Gly Ala Arg Phe Lys Asp He Asp Asn Ser 930 935 940 Lys Asn Leu Ser He Thr Thr Asn Ser Ser Ser Thr Tyr Arg Thr He 945 950 955 960 He Ser Gly Asn He Thr Asn Lys Asn Gly Asp Leu Asn He Thr Asn 965 970 975 Glu Gly Ser Asp Thr Glu Met Gin He Gly Gly Asp Val Ser Gin Lys 980 985 990 Glu Gly Asn Leu Thr He Ser Ser Asp Lys He Asn He Thr Lys Gin 995 1000 1005 He Thr He Lys Ala Gly Val Asp Gly Glu Asn Ser Asp Ser Asp Ala 1010 1015 1020 Thr Asn Asn Ala Asn Leu Thr He Lys Thr Lys Glu Leu Lys Leu Thr 1025 1030 1035 1040 Gin Asp Leu Asn He Ser Gly Phe Asn Lys Ala Glu He Thr Ala Lys 1045 1050 1055 Asp Gly Ser Asp Leu Thr He Gly Asn Thr Asn Ser Ala Asp Gly Thr 1060 1065 1070 Asn Ala Lys Lys Val Thr Phe Asn Gin Val Lys Asp Ser Lys He Ser 1075 1080 1085 Ala Asp Gly His Lys Val Thr Leu His Ser Lys Val Glu Thr Ser Gly 1090 1095 1100 Ser Asn Asn Asn Thr Glu Asp Ser Ser Asp Asn Asn Ala Gly Leu Thr 1105 1110 1115 1120 He Asp Ala Lys Asn Val Thr Val Asn Asn Asn He Thr Ser His Lys 1125 1130 1135 Ala Val Ser He Ser Ala Thr Ser Gly Glu He Thr Thr Lys Thr Gly 1140 1145 1150 Thr Thr He Asn Ala Thr Thr Gly Asn Val Glu He Thr Ala Gin Thr 1155 1160 1165 Gly Ser He Leu Gly Gly He Glu Ser Ser Ser Gly Ser Val Thr Leu 1170 1175 1180 Thr Ala Thr Glu Gly Ala Leu Ala Val Ser Asn He Ser Gly Asn Thr 1185 1190 1195 1200 Val Thr Val Thr Ala Asn Ser Gly Ala Leu Thr Thr Leu Ala Gly Ser 1205 1210 1215 Thr He Lys Gly Thr Glu Ser Val Thr Thr Ser Ser Gin Ser Gly Asp 1220 1225 1230 He Gly Gly Thr He Ser Gly Gly Thr Val Glu Val Lys Ala Thr Glu 1235 1240 1245 Ser Leu Thr Thr Gin Ser Asn Ser Lys He Lys Ala Thr Thr Gly Glu 1250 1255 1260 Ala Asn Val Thr Ser Ala Thr Gly Thr He Gly Gly Thr He Ser Gly 1265 1270 1275 1280 Asn Thr Val Asn Val Thr Ala Asn Ala Gly Asp Leu Thr Val Gly Asn 1285 1290 1295 Gly Ala Glu He Asn Ala Thr Glu Gly Ala Ala Thr Leu Thr Thr Ser 1300 1305 1310 Ser Gly Lys Leu Thr Thr Glu Ala Ser Ser His He Thr Ser Ala Lys 1315 1320 1325 Gly Gin Val Asn Leu Ser Ala Gin Asp Gly Ser Val Ala Gly Ser He 1330 1335 1340 Asn Ala Ala Asn Val Thr Leu Asn Thr Thr Gly Thr Leu Thr Thr Val 1345 1350 1355 1360 Lys Gly Ser Asn He Asn Ala Thr Ser Gly Thr Leu Val He Asn Ala 1365 1370 1375 Lys Asp Ala Glu Leu Asn Gly Ala Ala Leu Gly Asn His Thr Val Val 1380 1385 1390 Asn Ala Thr Asn Ala Asn Gly Ser Gly Ser Val He Ala Thr Thr Ser 1395 1400 1405 Ser Arg Val Asn He Thr Gly Asp Leu He Thr He Asn Gly Leu Asn 1410 1415 1420 He He Ser Lys Asn Gly He Asn Thr Val Leu Leu Lys Gly Val Lys 1425 1430 1435 1440 He Asp Val Lys Tyr He Gin Pro Gly He Ala Ser Val Asp Glu Val 1445 1450 1455 He Glu Ala Lys Arg He Leu Glu Lys Val Lys Asp Leu Ser Asp Glu 1460 1465 1470 Glu Arg Glu Ala Leu Ala Lys Leu Gly Val Ser Ala Val Arg Phe He 1475 1480 1485 Glu Pro Asn Asn Thr He Thr Val Asp Thr Gin Asn Glu Phe Ala Thr 1490 1495 1500 Arg Pro Leu Ser Arg He Val He Ser Glu Gly Arg Ala Cys Phe Ser 1505 1510 1515 1520 Asn Ser Asp Gly Ala Thr Val Cys Val Asn He Ala Asp Asn Gly Arg 1525 1530 1535 -„ " i u ' i - ir.tm' TUTE SHEET (RULE 26) (2) INFORMATION FOR SEQ ID NO:3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4937 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3: TAAATATACA AGATAATAAA AATAAATCAA GATTTTTGTG ATGACAAACA ACAATTACAA 60 CACCTTTTTT GCAGTCTATA TGCAAATATT TTAAAAAAAT AGTATAAATC CGCCATATAA 120 AATGGTATAA TCTTTCATCT TTCATCTTTA ATCTTTCATC TTTCATCTTT CATCTTTCAT 180 CTTTCATCTT TCATCTTTCA TCTTTCATCT TTCATCTTTC ATCTTTCATC TTTCATCTTT 240 CACATGAAAT GATGAACCGA GGGAAGGGAG GGAGGGGCAA GAATGAAGAG GGAGCTGAAC 300 GAACGCAAAT GATAAAGTAA TTTAATTGTT CAACTAACCT TAGGAGAAAA TATGAACAAG 360 ATATATCGTC TCAAATTCAG CAAACGCCTG AATGCTTTGG TTGCTGTGTC TGAATTGGCA 420 CGGGGTTGTG ACCATTCCAC AGAAAAAGGC TTCCGCTATG TTACTATCTT TAGGTGTAAC 480 CACTTAGCGT TAAAGCCACT TTCCGCTATG TTACTATCTT TAGGTGTAAC ATCTATTCCA 540 CAATCTGTTT TAGCAAGCGG CTTACAAGGA ATGGATGTAG TACACGGCAC AGCCACTATG 600 CAAGTAGATG GTAATAAAAC CATTATCCGC AACAGTGTTG ACGCTATCAT TAATTGGAAA 660 CAATTTAACA TCGACCAAAA TGAAATGGTG CAGTTTTTAC AAGAAAACAA CAACTCCGCC 720 GTATTCAACC GTGTTACATC TAACCAAATC TCCCAATTAA AAGGGATTTT AGATTCTAAC 780 GGACAAGTCT TTTTAATCAA CCCAAATGGT ATCACAATAG GTAAAGACGC AATTATTAAC 840 ACTAATGGCT TTACGGCTTC TACGCTAGAC ATTTCTAACG AAAACATCAA GGCGCGTAAT 900 TTCACCTTCG AGCAAACCAA AGATAAAGCG CTCGCTGAAA TTGTGAATCA CGGTTTAATT 960 ACTGTCGGTA AAGACGGCAG TGTAAATCTT ATTGGTGGCA AAGTGAAAAA CGAGGGTGTG 1020 ATTAGCGTAA ATGGTGGCAG CATTTCTTTA CTCGCAGGGC AAAAAATCAC CATCAGCGAT 1080 ATAATAAACC CAACCATTAC TTACAGCATT GCCGCGCCTG AAAATGAAGC GGTCAATCTG 1140 GGCGATATTT TTGCCAAAGG CGGTAACATT AATGTCCGTG CTGCCACTAT TCGAAACCAA 1200 GGTAAACTTT CTGCTGATTC TGTAAGCAAA GATAAAAGCG GCAATATTGT TCTTTCCGCC 1260 AAAGAGGGTG AAGCGGAAAT TGGCGGTGTA ATTTCCGCTC AAAATCAGCA AGCTAAAGGC 1320 GGCAAGCTGA TGATTACAGG CGATAAAGTC ACATTAAAAA CAGGTGCAGT TATCGACCTT 1380 TCAGGTAAAG AAGGGGGAGA AACTTACCTT GGCGGTGACG AGCGCGGCGA AGGTAAAAAC 1440 GGCATTCAAT TAGCAAAGAA AACCTCTTTA GAAAAAGGCT CAACCATCAA TGTATCAGGC 1500 AAAGAAAAAG GCGGACGCGC TATTGTGTGG GGCGATATTG CGTTAATTGA CGGCAATATT 1560 AACGCTCAAG GTAGTGGTGA TATCGCTAAA ACCGGTGGTT TTGTGGAGAC ATCGGGGCAT 1620 -E 26} TATTTATCCA TTGACAGCAA TGCAATTGTT AAAACAAAAG AGTGGTTGCT AGACCCTGAT 1680 GATGTAACAA TTGAAGCCGA AGACCCCCTT CGCAATAATA CCGGTATAAA TGATGAATTC 1740 CCAACAGGCA CCGGTGAAGC AAGCGACCCT AAAAAAAATA GCGAACTCAA AACAACGCTA 1800 ACCAATACAA CTATTTCAAA TTATCTGAAA AACGCCTGGA CAATGAATAT AACGGCATCA 1860 AGAAAACTTA CCGTTAATAG CTCAATCAAC ATCGGAAGCA ACTCCCACTT AATTCTCCAT 1920 AGTAAAGGTC AGCGTGGCGG AGGCGTTCAG ATTGATGGAG ATATTACTTC TAAAGGCGGA 1980 AATTTAACCA TTTATTCTGG CGGATGGGTT GATGTTCATA AAAATATTAC GCTTGATCAG 2040 GGTTTTTTAA ATATTACCGC CGCTTCCGTA GCTTTTGAAG GTGGAAATAA CAAAGCACGC 2100 GACGCGGCAA ATGCTAAAAT TGTCGCCCAG GGCACTGTAA CCATTACAGG AGAGGGAAAA 2160 GATTTCAGGG CTAACAACGT ATCTTTAAAC GGAACGGGTA AAGGTCTGAA TATCATTTCA 2220 TCAGTGAATA ATTTAACCCA CAATCTTAGT GGCACAATTA ACATATCTGG GAATATAACA 2280 ATTAACCAAA CTACGAGAAA GAACACCTCG TATTGGCAAA CCAGCCATGA TTCGCACTGG 2340 AACGTCAGTG CTCTTAATCT AGAGACAGGC GCAAATTTTA CCTTTATTAA ATACATTTCA 2400 AGCAATAGCA AAGGCTTAAC AACACAGTAT AGAAGCTCTG CAGGGGTGAA TTTTAACGGC 2460 GTAAATGGCA ACATGTCATT CAATCTCAAA GAAGGAGCGA AAGTTAATTT CAAATTAAAA 25 0 CCAAACGAGA ACATGAACAC AAGCAAACCT TTACCAATTC GGTTTTTAGC CAATATCACA 2580 GCCACTGGTG GGGGCTCTGT TTTTTTTGAT ATATATGCCA ACCATTCTGG CAGAGGGGCT 2640 GAGTTAAAAA TGAGTGAAAT TAATATCTCT AACGGCGCTA ATTTTACCTT AAATTCCCAT 2700 GTTCGCGGCG ATGACGCTTT TAAAATCAAC AAAGACTTAA CCATAAATGC AACCAATTCA 2760 AATTTCAGCC TCAGACAGAC GAAAGATGAT TTTTATGACG GGTACGCACG CAATGCCATC 2820 AATTCAACCT ACAACATATC CATTCTGGGC GGTAATGTCA CCCTTGGTGG ACAAAACTCA 2880 AGCAGCAGCA TTACGGGGAA TATTACTATC GAGAAAGCAG CAAATGTTAC GCTAGAAGCC 2940 AATAACGCCC CTAATCAGCA AAACATAAGG GATAGAGTTA TAAAACTTGG CAGCTTGCTC 3000 GTTAATGGGA GTTTAAGTTT AACTGGCGAA AATGCAGATA TTAAAGGCAA TCTCACTATT 3060 TCAGAAAGCG CCACTTTTAA AGGAAAGACT AGAGATACCC TAAATATCAC CGGCAATTTT 3120 ACCAATAATG GCACTGCCGA AATTAATATA ACACAAGGAG TGGTAAAACT TGGCAATGTT 3180 ACCAATGATG GTGATTTAAA CATTACCACT CACGCTAAAC GCAACCAAAG AAGCATCATC 3240 GGCGGAGATA TAATCAACAA AAAAGGAAGC TTAAATATTA CAGACAGTAA TAATGATGCT 3300 GAAATCCAAA TTGGCGGCAA TATCTCGCAA AAAGAAGGCA ACCTCACGAT TTCTTCCGAT 3360 AAAATTAATA TCACCAAACA GATAACAATC AAAAAGGGTA TTGATGGAGA GGACTCTAGT 3420 TCAGATGCGA CAAGTAATGC CAACCTAACT ATTAAAACCA AAGAATTGAA ATTGACAGAA 3480 GACCTAAGTA TTTCAGGTTT CAATAAAGCA GAGATTACAG CCAAAGATGG TAGAGATTTA 3540 ACTATTGGCA ACAGTAATGA CGGTAACAGC GGTGCCGAAG CCAAAACAGT AACTTTTAAC 3600 AATGTTAAAG ATTCAAAAAT CTCTGCTGAC GGTCACAATG TGACACTAAA TAGCAAAGTG 3660 BSTITUTE SHEET (RULE 26- AAAACATCTA GCAGCAATGG CGGACGTGAA AGCAATAGCG ACAACGATAC CGGCTTAACT 3720 ATTACTGCAA AAAATGTAGA AGTAAACAAA GATATTACTT CTCTCAAAAC AGTAAATATC 3780 ACCGCGTCGG AAAAGGTTAC CACCACAGCA GGCTCGACCA TTAACGCAAC AAATGGCAAA 3840 GCAAGTATTA CAACCAAAAC AGGTGATATC AGCGGTACGA TTTCCGGTAA CACGGTAAGT 3900 GTTAGCGCGA CTGGTGATTT AACCACTAAA TCCGGCTCAA AAATTGAAGC GAAATCGGGT 3960 GAGGCTAATG TAACAAGTGC AACAGGTACA ATTGGCGGTA CAATTTCCGG TAATACGGTA 4020 AATGTTACGG CAAACGCTGG CGATTTAACA GTTGGGAATG GCGCAGAAAT TAATGCGACA 4080 GAAGGAGCTG CAACCTTAAC CGCAACAGGG AATACCTTGA CTACTGAAGC CGGTTCTAGC 4140 ATCACTTCAA CTAAGGGTCA GGTAGACCTC TTGGCTCAGA ATGGTAGCAT CGCAGGAAGC 4200 ATTAATGCTG CTAATGTGAC ATTAAATACT ACAGGCACCT TAACCACCGT GGCAGGCTCG 4260 GATATTAAAG CAACCAGCGG CACCTTGGTT ATTAACGCAA AAGATGCTAA GCTAAATGGT 4320 GATGCATCAG GTGATAGTAC AGAAGTGAAT GCAGTCAACG CAAGCGGCTC TGGTAGTGTG 4380 ACTGCGGCAA CCTCAAGCAG TGTGAATATC ACTGGGGATT TAAACACAGT AAATGGGTTA 4440 AATATCATTT CGAAAGATGG TAGAAACACT GTGCGCTTAA GAGGCAAGGA AATTGAGGTG 4500 AAATATATCC AGCCAGGTGT AGCAAGTGTA GAAGAAGTAA TTGAAGCGAA ACGCGTCCTT 4560 GAAAAAGTAA AAGATTTATC TGATGAAGAA AGAGAAACAT TAGCTAAACT TGGTGTAAGT 4620 GCTGTACGTT TTGTTGAGCC AAATAATACA ATTACAGTCA ATACACAAAA TGAATTTACA 4680 ACCAGACCGT CAAGTCAAGT GATAATTTCT GAAGGTAAGG CGTGTTTCTC AAGTGGTAAT 4740 GGCGCACGAG TATGTACCAA TGTTGCTGAC GATGGACAGC CGTAGTCAGT AATTGACAAG 4800 GTAGATTTCA TCCTGCAATG AAGTCATTTT ATTTTCGTAT TATTTACTGT GTGGGTTAAA 4860 GTTCAGTACG GGCTTTACCC ATCTTGTAAA AAATTACGGA GAATACAATA AAGTATTTTT 4920 AACAGGTTAT TATTATG 4937 (2) INFORMATION FOR SEQ ID NO:4: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1477 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4: Met Asn Lys He Tyr Arg Leu Lys Phe Ser Lys Arg Leu Asn Ala Leu 1 5 10 15 Val Ala Val Ser Glu Leu Ala Arg Gly Cys Asp His Ser Thr Glu Lys 20 25 30 Gly Ser Glu Lys Pro Ala Arg Met Lys Val Arg His Leu Ala Leu Lys 35 40 45 USSTΠUTE SHEET (RULE 26) Pro Leu Ser Ala Met Leu Leu Ser Leu Gly Val Thr Ser He Pro Gin 50 55 60 Ser Val Leu Ala Ser Gly Leu Gin Gly Met Asp Val Val His Gly Thr 65 70 75 80 Ala Thr Met Gin Val Asp Gly Asn Lys Thr He He Arg Asn Ser Val 85 90 95 Asp Ala He He Asn Trp Lys Gin Phe Asn He Asp Gin Asn Glu Met 100 105 110 Val Gin Phe Leu Gin Glu Asn Asn Asn Ser Ala Val Phe Asn Arg Val 115 120 125 Thr Ser Asn Gin He Ser Gin Leu Lys Gly He Leu Asp Ser Asn Gly 130 135 140 Gin Val Phe Leu He Asn Pro Asn Gly He Thr He Gly Lys Asp Ala 145 150 155 160 He He Asn Thr Asn Gly Phe Thr Ala Ser Thr Leu Asp He Ser Asn 165 170 175 Glu Asn He Lys Ala Arg Asn Phe Thr Phe Glu Gin Thr Lys Asp Lys 180 185 190 Ala Leu Ala Glu He Val Asn His Gly Leu He Thr Val Gly Lys Asp 195 200 205 Gly Ser Val Asn Leu He Gly Gly Lys Val Lys Asn Glu Gly Val He 210 215 220 Ser Val Asn Gly Gly Ser He Ser Leu Leu Ala Gly Gin Lys He Thr 225 230 235 240 He Ser Asp He He Asn Pro Thr He Thr Tyr Ser He Ala Ala Pro 245 250 255 Glu Asn Glu Ala Val Asn Leu Gly Asp He Phe Ala Lys Gly Gly Asn 260 265 270 He Asn Val Arg Ala Ala Thr He Arg Asn Gin Gly Lys Leu Ser Ala 275 280 285 Asp Ser Val Ser Lys Asp Lys Ser Gly Asn He Val Leu Ser Ala Lys 290 295 300 Glu Gly Glu Ala Glu He Gly Gly Val He Ser Ala Gin Asn Gin Gin 305 310 315 320 Ala Lys Gly Gly Lys Leu Met He Thr Gly Asp Lys Val Thr Leu Lys 325 330 335 Thr Gly Ala Val He Asp Leu Ser Gly Lys Glu Gly Gly Glu Thr Tyr 340 345 350 Leu Gly Gly Asp Glu Arg Gly Glu Gly Lys Asn Gly He Gin Leu Ala 355 360 365 Lys Lys Thr Ser Leu Glu Lys Gly Ser Thr He Asn Val Ser Gly Lys 370 375 380 Glu Lys Gly Gly Phe Ala He Val Trp Gly Asp He Ala Leu He Asp 385 390 395 400 Gly Asn He Asn Ala Gin Gly Ser Gly Asp He Ala Lys Thr Gly Gly 405 410 415 Phe Val Glu Thr Ser Gly His Asp Leu Phe He Lys Asp Asn Ala He 420 425 430 Val Asp Ala Lys Glu Trp Leu Leu Asp Phe Asp Asn Val Ser He Asn 435 440 445 Ala Glu Asp Pro Leu Phe Asn Asn Thr Gly He Asn Asp Glu Phe Pro 450 455 460 Thr Gly Thr Gly Glu Ala Ser Asp Pro Lys Lys Asn Ser Glu Leu Lys 465 470 475 480 Thr Thr Leu Thr Asn Thr Thr He Ser Asn Tyr Leu Lys Asn Ala Trp 485 490 495 Thr Met Asn He Thr Ala Ser Arg Lys Leu Thr Val Asn Ser Ser He 500 505 510 Asn He Gly Ser Asn Ser His Leu He Leu His Ser Lys Gly Gin Arg 515 520 525 Gly Gly Gly Val Gin He Asp Gly Asp He Thr Ser Lys Gly Gly Asn 530 535 540 Leu Thr He Tyr Ser Gly Gly Trp Val Asp Val His Lys Asn He Thr 545 550 555 560 Leu Asp Gin Gly Phe Leu Asn He Thr Ala Ala Ser Val Ala Phe Glu 565 570 575 Gly Gly Asn Asn Lys Ala Arg Asp Ala Ala Asn Ala Lys He Val Ala 580 585 590 Gin Gly Thr Val Thr He Thr Gly Glu Gly Lys Asp Phe Arg Ala Asn 595 600 605 Asn Val Ser Leu Asn Gly Thr Gly Lys Gly Leu Asn He He Ser Ser 610 615 620 Val Asn Asn Leu Thr His Asn Leu Ser Gly Thr He Asn He Ser Gly 625 630 635 640 Asn He Thr He Asn Gin Thr Thr Arg Lys Asn Thr Ser Tyr Trp Gin 645 650 655 Thr Ser His Asp Ser His Trp Asn Val Ser Ala Leu Asn Leu Glu Thr 660 665 670 Gly Ala Asn Phe Thr Phe He Lys Tyr He Ser Ser Asn Ser Lys Gly 675 680 685 Leu Thr Thr Gin Tyr Arg Ser Ser Ala Gly Val Asn Phe Asn Gly Val 690 695 700 Asn Gly Asn Met Ser Phe Asn Leu Lys Glu Gly Ala Lys Val Asn Phe 705 710 715 720 Lys Leu Lys Pro Asn Glu Asn Met Asn Thr Ser Lys Pro Leu Pro He 725 730 735 Arg Phe Leu Ala Asn He Thr Ala Thr Gly Gly Gly Ser Val Phe Phe 740 745 750 i r" t ^ SUBSTITUTE SHEE * f-r. s 1 ϊ e*= Asp He Tyr Ala Asn His Ser Gly Arg Gly Ala Glu Leu Lys Met Ser 755 760 765 Glu He Asn He Ser Asn Gly Ala Asn Phe Thr Leu Asn Ser His Val 770 775 780 Arg Gly Asp Asp Ala Phe Lys He Asn Lys Asp Leu Thr He Asn Ala 785 790 795 800 Thr Asn Ser Asn Phe Ser Leu Arg Gin Thr Lys Asp Asp Phe Tyr Asp 805 810 815 Gly Tyr Ala Arg Asn Ala He Asn Ser Thr Tyr Asn He Ser He Leu 820 825 830 Gly Gly Asn Val Thr Leu Gly Gly Gin Asn Ser Ser Ser Ser He Thr 835 840 845 Gly Asn He Thr He Glu Lys Ala Ala Asn Val Thr Leu Glu Ala Asn 850 855 860 Asn Ala Pro Asn Gin Gin Asn He Arg Asp Arg Val He Lys Leu Gly 865 870 875 880 Ser Leu Leu Val Asn Gly Ser Leu Ser Leu Thr Gly Glu Asn Ala Asp 885 890 895 He Lys Gly Asn Leu Thr He Ser Glu Ser Ala Thr Phe Lys Gly Lys 900 905 910 Thr Arg Asp Thr Leu Asn He Thr Gly Asn Phe Thr Asn Asn Gly Thr 915 920 925 Ala Glu He Asn He Thr Gin Gly Val Val Lys Leu Gly Asn Val Thr 930 935 940 Asn Asp Gly Asp Leu Asn He Thr Thr His Ala Lys Arg Asn Gin Arg 945 950 955 960 Ser He He Gly Gly Asp He He Asn Lys Lys Gly Ser Leu Asn He 965 970 975 Thr Asp Ser Asn Asn Asp Ala Glu He Gin He Gly Gly Asn He Ser 980 985 990 Gin Lys Glu Gly Asn Leu Thr He Ser Ser Asp Lys He Asn He Thr 995 1000 1005 Lys Gin He Thr He Lys Lys Gly He Asp Gly Glu Asp Ser Ser Ser 1010 1015 1020 Asp Ala Thr Ser Asn Ala Asn Leu Thr He Lys Thr Lys Glu Leu Lys 1025 1030 1035 1040 Leu Thr Glu Asp Leu Ser He Ser Gly Phe Asn Lys Ala Glu He Thr 1045 1050 1055 Ala Lys Asp Gly Arg Asp Leu Thr He Gly Asn Ser Asn Asp Gly Asn 1060 1065 1070 Ser Gly Ala Glu Ala Lys Thr Val Thr Phe Asn Asn Val Lys Asp Ser 1075 1080 1085 Lys He Ser Ala Asp Gly His Asn Val Thr Leu Asn Ser Lys Val Lys 1090 1095 1100 Thr Ser Ser Ser Asn Gly Gly Arg Glu Ser Asn Ser Asp Asn Asp Thr 1105 1110 1115 1120 Gly Leu Thr He Thr Ala Lys Asn Val Glu Val Asn Lys Asp He Thr 1125 1130 1135 Ser Leu Lys Thr Val Asn He Thr Ala Ser Glu Lys Val Thr Thr Thr 1140 1145 1150 Ala Gly Ser Thr He Asn Ala Thr Asn Gly Lys Ala Ser He Thr Thr 1155 1160 1165 Lys Thr Gly Asp He Ser Gly Thr He Ser Gly Asn Thr Val Ser Val 1170 1175 1180 Ser Ala Thr Val Asp Leu Thr Thr Lys Ser Gly Ser Lys He Glu Ala 1185 1190 1195 1200 Lys Ser Gly Glu Ala Asn Val Thr Ser Ala Thr Gly Thr He Gly Gly 1205 1210 1215 Thr He Ser Gly Asn Thr Val Asn Val Thr Ala Asn Ala Gly Asp Leu 1220 1225 1230 Thr Val Gly Asn Gly Ala Glu He Asn Ala Thr Glu Gly Ala Ala Thr 1235 1240 1245 Leu Thr Ala Thr Gly Asn Thr Leu Thr Thr Glu Ala Gly Ser Ser He 1250 1255 1260 Thr Ser Thr Lys Gly Gin Val Asp Leu Leu Ala Gin Asn Gly Ser He 1265 1270 1275 1280 Ala Gly Ser He Asn Ala Ala Asn Val Thr Leu Asn Thr Thr Gly Thr 1285 1290 1295 Leu Thr Thr Val Ala Gly Ser Asp He Lys Ala Thr Ser Gly Thr Leu 1300 1305 1310 Val He Asn Ala Lys Asp Ala Lys Leu Asn Gly Asp Ala Ser Gly Asp 1315 1320 1325 Ser Thr Glu Val Asn Ala Val Asn Ala Ser Gly Ser Gly Ser Val Thr 1330 1335 1340 Ala Ala Thr Ser Ser Ser Val Asn He Thr Gly Asp Leu Asn Thr Val 1345 1350 1355 1360 Asn Gly Leu Asn He He Ser Lys Asp Gly Arg Asn Thr Val Arg Leu 1365 1370 1375 Arg Gly Lys Glu He Glu Val Lys Tyr He Gin Pro Gly Val Ala Ser 1380 1385 1390 Val Glu Glu Val He Glu Ala Lys Arg Val Leu Glu Lys Val Lys Asp 1395 1400 1405 Leu Ser Asp Glu Glu Arg Glu Thr Leu Ala Lys Leu Gly Val Ser Ala 1410 1415 1420 Val Arg Phe Val Glu Pro Asn Asn Thr He Thr Val Asn Thr Gin Asn 1425 1430 1435 1440 Glu Phe Thr Thr Arg Pro Ser Ser Gin Val He He Ser Glu Gly Lys 1445 1450 1455 IΠ TIT: JDO - . i ϋ Ε SHEET (RULE 26) Ala Cys Phe Ser Ser Gly Asn Gly Ala Arg Val Cys Thr Asn Val Ala 1460 1465 1470 Asp Asp Gly Gin Pro 1475 (2) INFORMATION FOR SEQ ID NO:5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 9171 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5: ACAGCGTTCT CTTAATACTA GTACAAACCC ACAATAAAAT ATGACAAACA ACAATTACAA 60 CACCTTTTTT GCAGTCTATA TGCAAATATT TTAAAAAATA GTATAAATCC GCCATATAAA 120 ATGGTATAAT CTTTCATCTT TCATCTTTCA TCTTTCATCT TTCATCTTTC ATCTTTCATC 180 TTTCATCTTT CATCTTTCAT CTTTCATCTT TCATCTTTCA TCTTTCATCT TTCATCTTTC 240 ACATGAAATG ATGAACCGAG GGAAGGGAGG GAGGGGCAAG AATGAAGAGG GAGCTGAACG 300 AACGCAAATG ATAAAGTAAT TTAATTGTTC AACTAACCTT AGGAGAAAAT ATGAACAAGA 360 TATATCGTCT CAAATTCAGC AAACGCCTGA ATGCTTTGGT TGCTGTGTCT GAATTGGCAC 420 GGGGTTGTGA CCATTCCACA GAAAAAGGCA GCGAAAAACC TGCTCGCATG AAAGTGCGTC 480 ACTTAGCGTT AAAGCCACTT TCCGCTATGT TACTATCTTT AGGTGTAACA TCTATTCCAC 540 AATCTGTTTT AGCAAGCGGC TTACAAGGAA TGGATGTAGT ACACGGCACA GCCACTATGC 600 AAGTAGATGG TAATAAAACC ATTATCCGCA ACAGTGTTGA CGCTATCATT AATTGGAAAC 660 AATTTAACAT CGACCAAAAT GAAATGGTGC AGTTTTTACA AGAAAACAAC AACTCCGCCG 720 TATTCAACCG TGTTACATCT AACCAAATCT CCCAATTAAA AGGGATTTTA GATTCTAACG 780 GACAAGTCTT TTTAATCAAC CCAAATGGTA TCACAATAGG TAAAGACGCA ATTATTAACA 840 CTAATGGCTT TACGGCTTCT ACGCTAGACA TTTCTAACGA AAACATCAAG GCGCGTAATT 900 TCACCTTCGA GCAAACCAAA GATAAAGCGC TCGCTGAAAT TGTGAATCAC GGTTTAATTA 960 CTGTCGGTAA AGACGGCAGT GTAAATCTTA TTGGTGGCAA AGTGAAAAAC GAGGGTGTGA 1020 TTAGCGTAAA TGGTGGCAGC ATTTCTTTAC TCGCAGGGCA AAAAATCACC ATCAGCGATA 1080 TAATAAACCC AACCATTACT TACAGCATTG CCGCGCCTGA AAATGAAGCG GTCAATCTGG 1140 GCGATATTTT TGCCAAAGGC GGTAACATTA ATGTCCGTGC TGCCACTATT CGAAACCAAG 1200 CTTTCCGCCA AAGAGGGTGA AGCGGAAATT GGCGGTGTAA TTTCCGCTCA AAATCAGCAA 1260 GCTAAAGGCG GCAAGCTGAT GATTACAGGC GATAAAGTCA CATTAAAAAC AGGTGCAGTT 1320 ATCGACCTTT CAGGTAAAGA AGGGGGAGAA ACTTACCTTG GCGGTGACGA GCGCGGCGAA 1380 GGTAAAAACG GCATTCAATT AGCAAAGAAA ACCTCTTTAG AAAAAGGCTC AACCATCAAT 1440 (**£*% SUBSTITUTE SHEET (RULE a» GTATCAGGCA AAGAAAAAGG CGGACGCGCT ATTGTGTGGG GCGATATTGC GTTAATTGAC 1500 GGCAATATTA ACGCTCAAGG TAGTGGTGAT ATCGCTAAAA CCGGTGGTTT TGTGGAGACG 1560 TCGGGGCATG ATTTATTCAT CAAAGACAAT GCAATTGTTG ACGCCAAAGA GTGGTTGTTA 1620 GACCCGGATA ATGTATCTAT TAATGCAGAA ACAGCAGGAC GCAGCAATAC TTCAGAAGAC 1680 GATGAATACA CGGGATCCGG GAATAGTGCC AGCACCCCAA AACGAAACAA AGAAAAGACA 1740 ACATTAACAA ACACAACTCT TGAGAGTATA CTAAAAAAAG GTACCTTTGT TAACATCACT 1800 GCTAATCAAC GCATCTATGT CAATAGCTCC ATTAATTTAT CCAATGGCAG CTTAACTCTT 1860 TGGAGTGAGG GTCGGAGCGG TGGCGGCGTT GAGATTAACA ACGATATTAC CACCGGTGAT 1920 GATACCAGAG GTGCAAACTT AACAATTTAC TCAGGCGGCT GGGTTGATGT TCATAAAAAT 1980 ATCTCACTCG GGGCGCAAGG TAACATAAAC ATTACAGCTA AACAAGATAT CGCCTTTGAG 2040 AAAGGAAGCA ACCAAGTCAT TACAGGTCAA GGGACTATTA CCTCAGGCAA TCAAAAAGGT 2100 TTTAGATTTA ATAATGTCTC TCTAAACGGC ACTGGCAGCG GACTGCAATT CACCACTAAA 2160 AGAACCAATA AATACGCTAT CACAAATAAA TTTGAAGGGA CTTTAAATAT TTCAGGGAAA 2220 GTGAACATCT CAATGGTTTT ACCTAAAAAT GAAAGTGGAT ATGATAAATT CAAAGGACGC 2280 ACTTACTGGA ATTTAACCTC GAAAGTGGAT ATGATAAATT CAAAGGACGC CCTCACTATT 2340 GACTCCAGAG GAAGCGATAG TGCAGGCACA CTTACCCAGC CTTATAATTT AAACGGTATA 2400 TCATTCAACA AAGACACTAC CTTTAATGTT GAACGAAATG CAAGAGTCAA CTTTGACATC 2460 AAGGCACCAA TAGGGATAAA TAAGTATTCT AGTTTGAATT ACGCATCATT TAATGGAAAC 2520 ATTTCAGTTT CGGGAGGGGG GAGTGTTGAT TTCACACTTC TCGCCTCATC CTCTAACGTC 2580 CAAACCCCCG GTGTAGTTAT AAATTCTAAA TACTTTAATG TTTCAACAGG GTCAAGTTTA 2640 AGATTTAAAA CTTCAGGCTC AACAAAAACT GGCTTCTCAA TAGAGAAAGA TTTAACTTTA 2700 AATGCCACCG GAGGCAACAT AACACTTTTG CAAGTTGAAG GCACCGATGG AATGATTGGT 2760 AAAGGCATTG TAGCCAAAAA AAACATAACC TTTGAAGGAG GTAAGATGAG GTTTGGCTCC 2820 AGGAAAGCCG TAACAGAAAT CGAAGGCAAT GTTACTATCA ATAACAACGC TAACGTCACT 2880 CTTATCGGTT CGGATTTTGA CAACCATCAA AAACCTTTAA CTATTAAAAA AGATGTCATC 2940 ATTAATAGCG GCAACCTTAC CGCTGGAGGC AATATTGTCA ATATAGCCGG AAATCTTACC 3000 GTTGAAAGTA ACGCTAATTT CAAAGCTATC ACAAATTTCA CTTTTAATGT AGGCGGCTTG 3060 TTTGACAACA AAGGCAATTC AAATATTTCC ATTGCCAAAG GAGGGGCTCG CTTTAAAGAC 3120 ATTGATAATT CCAAGAATTT AAGCATCACC ACCAACTCCA GCTCCACTTA CCGCACTATT 3180 ATAAGCGGCA ATATAACCAA TAAAAACGGT GATTTAAATA TTACGAACGA AGGTAGTGAT 3240 ACTGAAATGC AAATTGGCGG CGATGTCTCG CAAAAAGAAG GTAATCTCAC GATTTCTTCT 3300 GACAAAATCA ATATTACCAA ACAGATAACA ATCAAGGCAG GTGTTGATGG GGAGAATTCC 3360 GATTCAGACG CGACAAACAA TGCCAATCTA ACCATTAAAA CCAAAGAATT GAAATTAACG 3420 CAAGACCTAA ATATTTCAGG TTTCAATAAA GCAGAGATTA CAGCTAAAGA TGGTAGTGAT 3480 TTAACTATTG GTAACACCAA TAGTGCTGAT GGTACTAATG CCAAAAAAGT AACCTTTAAC 3540 CAGGTTAAAG ATTCAAAAAT CTCTGCTGAC GGTCACAAGG TGACACTACA CAGCAAAGTG 3600 GAΛACATCCG GTAGTAATAA CAACACTGAA GATAGCAGTG ACAATAATGC CGGCTTAACT 3660 ATCGATGCAA AAAATGTAAC AGTAAACAAC AATATTACTT CTCACAAAGC AGTGAGCATC 3720 TCTGCGACAA GTGGAGAAAT TACCACTAAA ACAGGTACAA CCATTAACGC AACCACTGGT 3780 AACGTGGAGA TAACCGCTCA AACAGGTAGT ATCCTAGGTG GAATTGAGTC CAGCTCTGGC 3840 TCTGTAACAC TTACTGCAAC CGAGGGCGCT CTTGCTGTAA GCAATATTTC GGGCAACACC 3900 GTTACTGTTA CTGCAAATAG CGGTGCATTA ACCACTTTGG CAGGCTCTAC AATTAAAGGA 3960 ACCGAGAGTG TAACCACTTC AAGTCAATCA GGCGATATCG GCGGTACGAT TTCTGGTGGC 4020 ACAGTAGAGG TTAAAGCAAC CGAAAGTTTA ACCACTCAAT CCAATTCAAA AATTAAAGCA 4080 ACAACAGGCG AGGCTAACGT AACAAGTGCA ACAGGTACAA TTGGTGGTAC GATTTCCGGT 4140 AATACGGTAA ATGTTACGGC AAACGCTGGC GATTTAACAG TTGGGAATGG CGCAGAAATT 4200 AATGCGACAG AAGGAGCTGC AACCTTAACT ACATCATCGG GCAAATTAAC TACCGAAGCT 4260 AGTTCACACA TTACTTCAGC CAAGGGTCAG GTAAATCTTT CAGCTCAGGA TGGTAGCGTT 4320 GCAGGAAGTA TTAATGCCGC CAATGTGACA CTAAATACTA CAGGCACTTT AACTACCGTG 4380 AAGGGTTCAA ACATTAATGC AACCAGCGGT ACCTTGGTTA TTAACGCAAA AGACGCTGAG 44 0 CTAAATGGCG CAGCATTGGG TAACCACACA GTGGTAAATG CAACCAACGC AAATGGCTCC 4500 GGCAGCGTAA TCGCGACAAC CTCAAGCAGA GTGAACATCA CTGGGGATTT AATCACAATA 4560 AATGGATTAA ATATCATTTC AAAAAACGGT ATAAACACCG TACTGTTAAA AGGCGTTAAA 4620 ATTGATGTGA AATACATTCA ACCGGGTATA GCAAGCGTAG ATGAAGTAAT TGAAGCGAAA 4680 CGCATCCTTG AGAAGGTAAA AGATTTATCT GATGAAGAAA GAGAAGCGTT AGCTAAACTT 4740 GGCGTAAGTG CTGTACGTTT TATTGAGCCA AATAATACAA TTACAGTCGA TACACAAAAT 4800 GAATTTGCAA CCAGACCATT AAGTCGAATA GTGATTTCTG AAGGCAGGGC GTGTTTCTCA 4860 AACAGTGATG GCGCGACGGT GTGCGTTAAT ATCGCTGATA ACGGGCGGTA GCGGTCAGTA 4920 ATTGACAAGG TAGATTTCAT CCTGCAATGA AGTCATTTTA TTTTCGTATT ATTTACTGTG 4980 TGGGTTAAAG TTCAGTACGG GCTTTACCCA TCTTGTAAAA AATTACGGAG AATACAATAA 5040 AGTATTTTTA ACAGGTTATT ATTATGAAAA ATATAAAAAG CAGATTAAAA CTCAGTGCAA 5100 TATCAGTATT GCTTGGCCTG GCTTCTTCAT CATTGTATGC AGAAGAAGCG TTTTTAGTAA 5160 AAGGCTTTCA GTTATCTGGT GCACTTGAAA CTTTAAGTGA AGACGCCCAA CTGTCTGTAG 5220 CAAAATCTTT ATCTAAATAC CAAGGCTCGC AAACTTTAAC AAACCTAAAA ACAGCACAGC 5280 TTGAATTACA GGCTGTGCTA GATAAGATTG AGCCAAATAA GTTTGATGTG ATATTGCCAC 5340 AACAAACCAT TACGGATGGC AATATTATGT TTGAGCTAGT CTCGAAATCA GCCGCAGAAA 5400 GCCAAGTTTT TTATAAGGCG AGCCAGGGTT ATAGTGAAGA AAATATCGCT CGTAGCCTGC 5460 CATCTTTGAA ACAAGGAAAA GTGTATGAAG ATGGTCGTCA GTGGTTCGAT TTGCGTGAAT 5520 SU SKt iLE 26 ! TCAATATGGC AAAAGAAAAT CCACTTAAAG TCACTCGCGT GCATTACGAG TTAAACCCTA 5580 AAAACAAAAC CTCTGATTTG GTAGTTGCAG GTTTTTCGCC TTTTGGCAAA ACGCGTAGCT 5640 TTGTTTCCTA TGATAATTTC GGCGCAAGGG AGTTTAACTA TCAACGTGTA AGTCTAGGTT 5700 TTGTAAATGC CAATTTGACC GGACATGATG ATGTATTAAA TCTAAACGCA TTGACCAATG 5760 TAAAAGCACC ATCAAAATCT TATGCGGTAG GCATAGGATA TACTTATCCG TTTTATGATA 5820 AACACCAATC CTTAAGTCTT TATACCAGCA TGAGTTATGC TGATTCTAAT GATATCGACG 5880 GCTTACCAAG TGCGATTAAT CGTAAATTAT CAAAAGGTCA ATCTATCTCT GCGAATCTGA 59 0 AATGGAGTTA TTATCTCCCG ACATTTAACC TTGGAATGGA AGACCAGTTT AAAATTAATT 6000 TAGGCTACAA CTACCGCCAT ATTAATCAAA CATCCGAGTT AAACACCCTG GGTGCAACGA 6060 AGAAAAAATT TGCAGTATCA GGCGTAAGTG CAGGCATTGA TGGACATATC CAATTTACCC 6120 CTAAAACAAT CTTTAATATT GATTTAACTC ATCATTATTA CGCGAGTAAA TTACCAGGCT 6180 CTTTTGGAAT GGAGCGCATT GGCGAAACAT TTAATCGCAG CTATCACATT AGCACAGCCA 6240 GTTTAGGGTT GAGTCAAGAG TTTGCTCAAG GTTGGCATTT TAGCAGTCAA TTATCGGGTC 6300 AGTTTACTCT ACAAGATATA AGTAGCATAG ATTTATTCTC TGTAACAGGT ACTTATGGCG 6360 TCAGAGGCTT TAAATACGGC GGTGCAAGTG GTGAGCGCGG TCTTGTATGG CGTAATGAAT 6420 TAAGTATGCC AAAATACACC CGCTTTCAAA TCAGCCCTTA TGCGTTTTAT GATGCAGGTC 6480 AGTTCCGTTA TAATAGCGAA AATGCTAAAA CTTACGGCGA AGATATGCAC ACGGTATCCT 6540 CTGCGGGTTT AGGCATTAAA ACCTCTCCTA CACAAAACTT AAGCTTAGAT GCTTTTGTTG 6600 CTCGTCGCTT TGCAAATGCC AATAGTGACA ATTTGAATGG CAACAAAAAA CGCACAAGCT 6660 CACCTACAAC CTTCTGGGGT AGATTAACAT TCAGTTTCTA ACCCTGAAAT TTAATCAACT 6720 GGTAAGCGTT CCGCCTACCA GTTTATAACT ATATGCTTTA CCCGCCAATT TACAGTCTAT 6780 ACGCAACCCT GTTTTCATCC TTATATATCA AACAAACTAA GCAAACCAAG CAAACCAAGC 68 0 AAACCAAGCA AACCAAGCAA ACCAAGCAAA CCAAGCAAAC CAAGCAAACC AAGCAAACCA 6900 AGCAAACCAA GCAAACCAAG CAAACCAAGC AAACCAAGCA ATGCTAAAAA ACAATTTATA 6960 TGATAAACTA AAACATACTC CATACCATGG CAATACAAGG GATTTAATAA TATGACAAAA 7020 GAAAATTTAC AAAGTGTTCC ACAAAATACG ACCGCTTCAC TTGTAGAATC AAACAACGAC 7080 CAAACTTCCC TGCAAATACT TAAACAACCA CCCAAACCCA ACCTATTACG CCTGGAACAA 7140 CATGTCGCCA AAAAAGATTA TGAGCTTGCT TGCCGCGAAT TAATGGCGAT TTTGGAAAAA 7200 ATGGACGCTA ATTTTGGAGG CGTTCACGAT ATTGAATTTG ACGCACCTGC TCAGCTGGCA 7260 TATCTACCCG AAAAACTACT AATTCATTTT GCCACTCGTC TCGCTAATGC AATTACAACA 7320 CTCTTTTCCG ACCCCGAATT GGCAATTTCC GAAGAAGGGG CATTAAAGAT GATTAGCCTG 7380 CAACGCTGGT TGACGCTGAT TTTTGCCTCT TCCCCCTACG TTAACGCAGA CCATATTCTC 7440 AATAAATATA ATATCAACCC AGATTCCGAA GGTGGCTTTC ATTTAGCAAC AGACAACTCT 7500 TCTATTGCTA AATTCTGTAT TTTTTACTTA CCCGAATCCA ATGTCAATAT GAGTTTAGAT 7560 ςi inc STi TΞ SHEET (RULE 26) GCGTTATGGG CAGGGAATCA ACAACTTTGT GCTTCATTGT GTTTTGCGTT GCAGTCTTCA 7620 CGTTTTATTG GTACTGCATC TGCGTTTCAT AAAAGAGCGG TGGTTTTACA GTGGTTTCCT 7680 AAAAAACTCG CCGAAATTGC TAATTTAGAT GAATTGCCTG CAAATATCCT TCATGATGTA 7740 TATATGCACT GCAGTTATGA TTTAGCΛAAA AACAAGCACG ATGTTAAGCG TCCATTAAAC 7800 GAACTTGTCC GCAAGCATAT CCTCACGCAA GGATGGCAAG ACCGCTACCT TTACACCTTA 7860 GGTAAAAAGG ACGGCAAACC TGTGATGATG GTACTGCTTG AACATTTTAA TTCGGGACAT 7920 TCGATTTATC GCACGCATTC AACTTCAATG ATTGCTGCTC GAGAAAAATT CTATTTAGTC 7980 GGCTTAGGCC ATGAGGGCGT TGATAACATA GGTCGAGAAG TGTTTGACGA GTTCTTTGAA 8040 ATCAGTAGCA ATAATATAAT GGAGAGACTG TTTTTTATCC GTAAACAGTG CGAAACTTTC 8100 CAACCCGCAG TGTTCTATAT GCCAAGCATT GGCATGGATA TTACCACGAT TTTTGTGAGC 8160 AACACTCGGC TTGCCCCTAT TCAAGCTGTA GCCTTGGGTC ATCCTGCCAC TACGCATTCT 8220 GAATTTATTG ATTATGTCAT CGTAGAAGAT GATTATGTGG GCAGTGAAGA TTGTTTTAGC 8280 GAAACCCTTT TACGCTTACC CAAAGATGCC CTACCTTATG TACCATCTGC ACTCGCCCCA 8340 CAAAAAGTGG ATTATGTACT CAGGGAAAAC CCTGAAGTAG TCAATATCGG TATTGCCGCT 8400 ACCACAATGA AATTAAACCC TGAATTTTTG CTAACATTGC AAGAAATCAG AGATAAAGCT 8460 AAAGTCAAAA TACATTTTCA TTTCGCACTT GGACAATCAA CAGGCTTGAC ACACCCTTAT 8520 GTCAAATGGT TTATCGAAAG CTATTTAGGT GACGATGCCA CTGCACATCC CCACGCACCT 8580 TATCACGATT ATCTGGCAAT ATTGCGTGAT TGCGATATGC TACTAAATCC GTTTCCTTTC 8640 GGTAATACTA ACGGCATAAT TGATATGGTT ACATTAGGTT TAGTTGGTGT ATGCAAAACG 8700 GGGGATGAAG TACATGAACA TATTGATGAA GGTCTGTTTA AACGCTTAGG ACTACCAGAA 8760 TGGCTGATAG CCGACACACG AGAAACATAT ATTGAATGTG CTTTGCGTCT AGCAGAAAAC 8820 CATCAAGAAC GCCTTGAACT CCGTCGTTAC ATCATAGAAA ACAACGGCTT ACAAAAGCTT 8880 TTTACAGGCG ACCCTCGTCC ATTGGGCAAA ATACTGCTTA AGAAAACAAA TGAATGGAAG 8940 CGGAAGCACT TGAGTAAAAA ATAACGGTTT TTTAAAGTAA AAGTGCGGTT AATTTTCAAA 9000 GCGTTTTAAA AACCTCTCAA AAATCAACCG CACTTTTATC TTTATAACGC TCCCGCGCGC 9060 TGACAGTTTA TCTCTTTCTT AAAATACCCA TAAAATTGTG GCAATAGTTG GGTAATCAAA 9120 TTCAATTGTT GATACGGCAA ACTAAAGACG GCGCGTTCTT CGGCAGTCAT C 9171 (2) INFORMATION FOR SEQ ID NO:6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 9323 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE : DNA (genomic) af - ;«. ; S P-"""" 1 -« *--«, fr", - → →" (RULE 2δ (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6 : CGCCACTTCA ATTTTGGATT GTTGAAATTC AACTAACCAA AAAGTGCGGT TAAAATCTGT 60 GGAGAAAATA GGTTGTAGTG AAGAACGAGG TAATTGTTCA AAAGGATAAA GCTCTCTTAA 120 TTGGGCAΪTG GTTGGCGTTT CTTTTTCGGT TAATAGTAAA TTATATTCTG GACGACTATG 180 CAATCCACCA ACAACTTTAC CGTTGGTTTT AAGCGTTAAT GTAAGTTCTT GCTCTTCTTG 240 GCGAATACGT AATCCCATTT TTTGTTTAGC AAGAAAATGA TCGGGATAAT CATAATAGGT 300 GTTGCCCAAA AATAAATTTT GATGTTCTAA AATCATAAAT TTTGCAAGAT ATTGTGGCAA 360 TTCAATACCT ATTTGTGGCG AAATCGCCAA TTTTAATTCA ATTTCTTGTA GCATAATATT 420 TCCCACTCAA ATCAACTGGT TAAATATACA AGATAATAAA AATAAATCAA GATTTTTGTG 480 ATGACAAACA ACAATTACAA CACCTTTTTT GCAGTCTATA TGCAAATATT TTAAAAAAAT 540 AGTATAAATC CGCCATATAA AATGGTATAA TCTTTCATCT TTCATCTTTC ATCTTTCATC 600 TTTCATCTTT CATCTTTCAT CTTTCATCTT TCATCTTTCA TCTTTCATCT TTCATCTTTC 660 ATCTTTCATC TTTCATCTTT CACATGAAAT GATGAACCGA GGGAAGGGAG GGAGGGGCAA 720 GAATGAAGAG GGAGCTGAAC GAACGCAAAT GATAAAGTAA TTTAATTGTT CAACTAACCT 780 TAGGAGAAAA TATGAACAAG ATATATCGTC TCAAATTCAG CAAACGCCTG AATGCTTTGG 840 TTGCTGTGTC TGAATTGGCA CGGGGTTGTG ACCATTCCAC AGAAAAAGGC AGCGAAAAAC 900 CTGCTCGCAT GAAAGTGCGT CACTTAGCGT TAAAGCCACT TTCCGCTATG TTACTATCTT 960 TAGGTGTAAC ATCTATTCCA CAATCTGTTT TAGCAAGCGG CAATTTAACA TCGACCAAAA 1020 TGAAATGGTG CAGTTTTTAC AAGAAAACAA GTAATAAAAC CATTATCCGC AACAGTGTTG 1080 ACGCTATCAT TAATTGGAAA CAATTTAACA TCGACCAAAA TGAAATGGTG CAGTTTTTAC 1140 AAGAAAACAA CAACTCCGCC GTATTCAACC GTGTTACATC TAACCAAATC TCCCAATTAA 1200 AAGGGATTTT AGATTCTAAC GGACAAGTCT TTTTAATCAA CCCAAATGGT ATCACAATAG 1260 GTAAAGACGC AATTATTAAC ACTAATGGCT TTACGGCTTC TACGCTAGAC ATTTCTAACG 1320 AAAACATCAA GGCGCGTAAT TTCACCTTCG AGCAAACCAA AGATAAAGCG CTCGCTGAAA 1380 TTGTGAATCA CGGTTTAATT ACTGTCGGTA AAGACGGCAG TGTAAATCTT ATTGGTGGCA 1440 AAGTGAAAAA CGAGGGTGTG ATTAGCGTAA ATGGTGGCAG CATTTCTTTA CTCGCAGGGC 1500 AAAAAATCAC CATCAGCGAT ATAATAAACC CAACCATTAC TTACAGCATT GCCGCGCCTG 1560 AAAATGAAGC GGTCAATCTG GGCGATATTT TTGCCAAAGG CGGTAACATT AATGTCCGTG 1620 CTGCCACTAT TCGAAACCAA GGTAAACTTT CTGCTGATTC TGTAAGCAAA GATAAAAGCG 1680 GCAATATTGT TCTTTCCGCC AAAGAGGGTG AAGCGGAAAT TGGCGGTGTA ATTTCCGCTC 1740 AAAATCAGCA AGCTAAAGGC GGCAAGCTGA TGATAAAGTC CGATAAAGTC ACATTAAAAA 1800 CAGGTGCAGT TATCGACCTT TCAGGTAAAG AAGGGGGAGA AACTTACCTT GGCGGTGACG 1860 AGCGCGGCGA AGGTAAAAAC GGCATTCAAT TAGCAAAGAA AACCTCTTTA GAAAAAGGCT 1920 CAACCATCAA TGTATCAGGC AAAGAAAAAG GCGGACGCGC TATTGTGTGG GGCGATATTG 1980 CGTTAATTGA CGGCAATATT AACGCTCAAG GTAGTGGTGA TATCGCTAAA ACCGGTGGTT 2040 TTGTGGAGAC ATCGGGGCAT TATTTATCCA TTGACAGCAA TGCAATTGTT AAAACAAAAG 2100 AGTGGTTGCT AGACCCTGAT GATGTAACAA TTGAAGCCGA AGACCCCCTT CGCAATAATA 2160 CCGGTATAAA TGATGAATTC CCAACAGGCA CCGGTGAAGC AAGCGACCCT AAAAAAAATA 2220 GCGAACTCAA AACAACGCTA ACCAATACAA CTATTTCAAA TTATCTGAAA AACGCCTGGA 2280 CAATGAATAT AACGGCATCA AGAAAACTTA CCGTTAATAG CTCAATCAAC ATCGGAAGCA 2340 ACTCCCACTT AATTCTCCAT AGTAAAGGTC AGCGTGGCGG AGGCGTTCAG ATTGATGGAG 2400 ATATTACTTC TAAAGGCGGA AATTTAACCA TTTATTCTGG CGGATGGGTT GATGTTCATA 2460 AAAATATTAC GCTTGATCAG GGTTTTTTAA ATATTACCGC CGCTTCCGTA GCTTTTGAAG 2520 GTGGAAATAA CAAAGCACGC GACGCGGCAA ATGCTAAAAT TGTCGCCCAG GGCACTGTAA 2580 CCATTACAGG AGAGGGAAAA GATTTCAGGG CTAACAACGT ATCTTTAAAC GGAACGGGTA 2640 AAGGTCTGAA TATCATTTCA TCAGTGAATA ATTTAACCCA CAATCTTAGT GGCACAATTA 2700 ACATATCTGG GAATATAACA ATTAACCAAA CTACGAGAAA GAACACCTCG TATTGGCAAA 2760 CCAGCCATGA TTCGCACTGG AACGTCAGTG CTCTTAATCT AGAGACAGGC GCAAATTTTA 2820 CCTTTATTAA ATACATTTCA AGCAATAGCA AAGGCTTAAC AACACAGTAT AGAAGCTCTG 2880 CAGGGGTGAA TTTTAACGGC GTAAATGGCA ACATGTCATT CAATCTCAAA GAAGGAGCGA 2940 AAGTTAATTT CAAATTAAAA CCAAACGAGA ACATGAACAC AAGCAAACCT TTACCAATTC 3000 GGTTTTTAGC CAATATCACA GCCACTGGTG GGGGCTCTGT TTTTTTTGAT ATATATGCCA 3060 ACCATTCTGG CAGAGGGGCT GAGTTAAAAA TGAGTGAAAT TAATATCTCT AACGGCGCTA 3120 ATTTTACCTT AAATTCCCAT GTTCGCGGCG ATGACGCTTT TAAAATCAAC AAAGACTTAA 3180 CCATAAATGC AACCAATTCA AATTTCAGCC TCAGACAGAC GAAAGATGAT TTTTATGACG 3240 GGTACGCACG CAATGCCATC AATTCAACCT ACAACATATC CATTCTGGGC GGTAATGTCA 3300 CCCTTGGTGG ACAAAACTCA AGCAGCAGCA TTACGGGGAA TATTACTATC GAGAAAGCAG 3360 CAAATGTTAC GCTAGAAGCC AATAACGCCC CTAATCAGCA AAACATAAGG GATAGAGTTA 3420 TAAAACTTGG CAGCTTGCTC GTTAATGGGA GTTTAAGTTT AACTGGCGAA AATGCAGATA 3480 TTAAAGGCAA TCTCACTATT TCAGAAAGCG CCACTTTTAA AGGAAAGACT AGAGATACCC 3540 TAAATATCAC CGGCAATTTT ACCAATAATG GCACTGCCGA AATTAATATA ACACAAGGAG 3600 TGGTAAAACT TGGCAATGTT ACCAATGATG GTGATTTAAA CATTACCACT CACGCTAAAC 3660 GCAACCAAAG AAGCATCATC GGCGGAGATA TAATCAACAA AAAAGGAAGC TTAAATATTA 3720 CAGACAGTAA TAATGATGCT GAAATCCAAA TTGGCGGCAA TATCTCGCAA AAAGAAGGCA 3780 ACCTCACGAT TTCTTCCGAT AAAATTAATA TCACCAAACA GATAACAATC AAAAAGGGTA 3840 TTGATGGAGA GGACTCTAGT TCAGATGCGA CAAGTAATGC CAACCTAACT ATTAAAACCA 3900 AAGAATTGAA ATTGACAGAA GACCTAAGTA TTTCAGGTTT CAATAAAGCA GAGATTACAG 3960 CCAAAGATGG TAGAGATTTA ACTATTGGCA ACAGTAATGA CGGTAACAGC GGTGCCGAAG 4020 CCAAAACAGT AACTTTTAAC AATGTTAAAG ATTCAAAAAT CTCTGCTGAC GGTCACAATG 4080 TGACACTAAA TAGCAAAGTG AAAACATCTA GCAGCAATGG CGGACGTGAA AGCAATAGCG 4140 ACAACGATAC CGGCTTAACT ATTACTGCAA AAAATGTAGA AGTAAACAAA GATATTACTT 4200 CTCTCAAAAC AGTAAATATC ACCGCGTCGG AAAAGGTTAC CACCACAGCA GGCTCGACCA 4260 TTAACGCAAC AAATGGCAAA GCAAGTATTA CAACCAAAAC AGGTGATATC AGCGGTACGA 4320 TTTCCGGTAA CACGGTAAGT GTTAGCGCGA CTGGTGATTT AACCACTAAA TCCGGCTCAA 4380 AAATTGAAGC GAAATCGGGT GAGGCTAATG TAACAAGTGC AACAGGTACA ATTGGCGGTA 4440 CAATTTCCGG TAATACGGTA AATGTTACGG CAAACGCTGG CGATTTAACA GTTGGGAATG 4500 GCGCAGAAAT TAATGCGACA GAAGGAGCTG CAACCTTAAC CGCAACAGGG AATACCTTGA 4560 CTACTGAAGC CGGTTCTAGC ATCACTTCAA CTAAGGGTCA GGTAGACCTC TTGGCTCAGA 4620 ATGGTAGCAT CGCAGGAAGC ATTAATGCTG CTAATGTGAC ATTAAATACT ACAGGCACCT 4680 TAACCACCGT GGCAGGCTCG GATATTAAAG CAACCAGCGG CACCTTGGTT ATTAACGCAA 4740 AAGATGCTAA GCTAAATGGT GATGCATCAG GTGATAGTAC AGAAGTGAAT GCAGTCAACG 4800 ACTGGGGATT TGGTAGTGTG ACTGCGGCAA CCTCAAGCAG TGTGAATATC ACTGGGGATT 4860 TAAACACAGT AAATGGGTTA AATATCATTT CGAAAGATGG TAGAAACACT GTGCGCTTAA 4920 GAGGCAAGGA AATTGAGGTG AAATATATCC AGCCAGGTGT AGCAAGTGTA GAAGAAGTAA 4980 TTGAAGCGAA ACGCGTCCTT GAAAAAGTAA AAGATTTATC TGATGAAGAA AGAGAAACAT 5040 TAGCTAAACT TGGTGTAAGT GCTGTACGTT TTGTTGAGCC AAATAATACA ATTACAGTCA 5100 ATACACAAAA TGAATTTACA ACCAGACCGT CAAGTCAAGT GATAATTTCT GAAGGTAAGG 5160 CGTGTTTCTC AAGTGGTAAT GGCGCACGAG TATGTACCAA TGTTGCTGAC GATGGACAGC 5220 CGTAGTCAGT AATTGACAAG GTAGATTTCA TCCTGCAATG AAGTCATTTT ATTTTCGTAT 5280 TATTTACTGT GTGGGTTAAA GTTCAGTACG GGCTTTACCC ATCTTGTAAA AAATTACGGA 5340 GAATACAATA AAGTATTTTT AACAGGTTAT TATTATGAAA AATATAAAAA GCAGATTAAA 5400 ACTCAGTGCA ATATCAGTAT TGCTTGGCCT GGCTTCTTCA TCATTGTATG CAGAAGAAGC 5460 GTTTTTAGTA AAAGGCTTTC AGTTATCTGG TGCACTTGAA ACTTTAAGTG AAGACGCCCA 5520 ACTGTCTGTA GCAAAATCTT TATCTAAATA CCAAGGCTCG CAAACTTTAA CAAACCTAAA 5580 AACAGCACAG CTTGAATTAC AGGCTGTGCT AGATAAGATT GAGCCAAATA AATTTGATGT 5640 GATATTGCCG CAACAAACCA TTACGGATGG CAATATCATG TTTGAGCTAG TCTCGAAATC 5700 AGCCGCAGAA AGCCAAGTTT TTTATAAGGC GAGCCAGGGT TATAGTGAAG AAAATATCGC 5760 TCGTAGCCTG CCATCTTTGA AACAAGGAAA AGTGTATGAA GATGGTCGTC AGTGGTTCGA 5820 TTTGCGTGAA TTTAATATGG CAAAAGAAAA CCCGCTTAAG GTTACCCGTG TACATTACGA 5880 ACTAAACCCT AAAAACAAAA CCTCTAATTT GATAATTGCG GGCTTCTCGC CTTTTGGTAA 5940 AACGCGTAGC TTTATTTCTT ATGATAATTT CGGCGCGAGA GAGTTTAACT ACCAACGTGT 6000 AAGCTTGGGT TTTGTTAATG CCAATTTAAC TGGTCATGAT GATGTGTTAA TTATACCAGT 6060 , ic rϊTϊ *TP HPF7 ' RULE 26} ATGAGTTATG CTGATTCTAA TGATATCGAC GGCTTACCAA GTGCGATTAA TCGTAAATTA 6120 TCAAAAGGTC AATCTATCTC TGCGAATCTG AAATGGAGTT ATTATCTCCC AACATTTAAC 6180 CTTGGCATGG AAGACCAATT TAAAATTAAT TTAGGCTACA ACTACCGCCA TATTAATCAA 6240 ACCTCCGCGT TAAATCGCTT GGGTGAAACG AAGAAAAAAT TTGCAGTATC AGGCGTAAGT 6300 GCAGGCATTG ATGGACATAT CCAATTTACC CCTAAAACAA TCTTTAATAT TGATTTAACT 6360 CATCATTATT ACGCGAGTAA ATTACCAGGC TCTTTTGGAA TGGAGCGCAT TGGCGAAACA 6420 TTTAATCGCA GCTATCACAT TAGCACAGCC AGTTTAGGGT TGAGTCAAGA GTTTGCTCAA 6480 GGTTGGCATT TTAGCAGTCA ATTATCAGGT CAATTTACTC TACAAGATAT TAGCAGTATA 6540 GATTTATTCT CTGTAACAGG TACTTATGGC GTCAGAGGCT TTAAATACGG CGGTGCAAGT 6600 GGTGAGCGCG GTCTTGTATG GCGTAATGAA TTAAGTATGC CAAAATACAC CCGCTTCCAA 6660 ATCAGCCCTT ATGCGTTTTA TGATGCAGGT CAGTTCCGTT ATAATAGCGA AAATGCTAAA 6720 ACTTACGGCG AAGATATGCA CACGGTATCC TCTGCGGGTT TAGGCATTAA AACCTCTCCT 6780 ACACAAAACT TAAGCCTAGA TGCTTTTGTT GCTCGTCGCT TTGCAAATGC CAATAGTGAC 6840 AATTTGAATG GCAACAAAAA ACGCACAAGC TCACCTACAA CCTTCTGGGG GAGATTAACA 6900 TTCAGTTTCT AACCCTGAAA TTTAATCAAC TGGTAAGCGT TCCGCCTACC AGTTTATAAC 6960 TATATGCTTT ACCCGCCAAT TTACAGTCTA TAGGCAACCC TGTTTTTACC CTTATATATC 7020 AAATAAACAA GCTAAGCTGA GCTAAGCAAA CCAAGCAAAC TCAAGCAAGC CAAGTAATAC 7080 TAAAAAAACA ATTTATATGA TAAACTAAAG TATACTCCAT GCCATGGCGA TACAAGGGAT 7140 TTAATAATAT GACAAAAGAA AATTTGCAAA ACGCTCCTCA AGATGCGACC GCTTTACTTG 7200 CGGAATTAAG CAACAATCAA ACTCCCCTGC GAATATTTAA ACAACCACGC AAGCCCAGCC 7260 TATTACGCTT GGAACAACAT ATCGCAAAAA AAGATTATGA GTTTGCTTGT CGTGAATTAA 7320 TGGTGATTCT GGAAAAAATG GACGCTAATT TTGGAGGCGT TCACGATATT GAATTTGACG 7380 CACCCGCTCA GCTGGCATAT CTACCCGAAA AATTACTAAT TTATTTTGCC ACTCGTCTCG 7440 CTAATGCAAT TACAACACTC TTTTCCGACC CCGAATTGGC AATTTCTGAA GAAGGGGCGT 7500 TAAAGATGAT TAGCCTGCAA CGCTGGTTGA CGCTGATTTT TGCCTCTTCC CCCTACGTTA 7560 ACGCAGACCA TATTCTCAAT AAATATAATA TCAACCCAGA TTCCGAAGGT GGCTTTCATT 7620 TAGCAACAGA CAACTCTTCT ATTGCTAAAT TCTGTATTTT TTACTTACCC GAATCCAATG 7680 TCAATATGAG TTTAGATGCG TTATGGGCAG GGAATCAACA ACTTTGTGCT TCATTGTGTT 7740 TTGCGTTGCA GTCTTCACGT TTTATTGGTA CCGCATCTGC GTTTCATAAA AGAGCGGTGG 7800 TTTTACAGTG GTTTCCTAAA AAACTCGCCG AAATTGCTAA TTTAGATGAA TTGCCTGCAA 7860 ATATCCTTCA TGATGTATAT ATGCACTGCA GTTATGATTT AGCAAAAAAC AAGCACGATG 7920 TTAAGCGTCC ATTAAACGAA CTTGTCCGCA AGCATATCCT CACGCAAGGA TGGCAAGACC 7980 GCTACCTTTA CACCTTAGGT AAAAAGGACG GCAAACCTGT GATGATGGTA CTGCTTGAAC 8040 ATTTTAATTC GGGACATTCG ATTTATCGTA CACATTCAAC TTCAATGATT GCTGCTCGAG 8100 AAAAATTCTA TTTAGTCGGC TTAGGCCATG AGGGCGTTGA TAAAATAGGT CGAGAAGTGT 8160 TTGACGAGTT CTTTGAAATC AGTAGCAATA ATATAATGGA GAGACTGTTT TTTATCCGTA 8220 AACAGTGCGA AACTTTCCAA CCCGCAGTGT TCTATATGCC AAGCATTGGC ATGGATATTA 8280 CCACGATTTT TGTGAGCAAC ACTCGGCTTG CCCCTATTCA AGCTGTAGCC CTGGGTCATC 83 0 CTGCCACTAC GCATTCTGAA TTTATTGATT ATGTCATCGT AGAAGATGAT TATGTGGGCA 8400 GTGAAGATTG TTTCAGCGAA ACCCTTTTAC GCTTACCCAA AGATGCCCTA CCTTATGTAC 8460 CTTCTGCACT CGCCCCACAA AAAGTGGATT ATGTACTCAG GGAAAACCCT GAAGTAGTCA 8520 ATATCGGTAT TGCCGCTACC ACAATGAAAT TAAACCCTGA ATTTTTGCTA ACATTGCAAG 8580 AAATCAGAGA TAAAGCTAAA GTCAAAATAC ATTTTCATTT CGCACTTGGA CAATCAACAG 8640 GCTTGACACA CCCTTATGTC AAATGGTTTA TCGAAAGCTA TTTAGGTGAC GATGCCACTG 8700 CACATCCCCA CGCACCTTAT CACGATTATC TGGCAATATT GCGTGATTGC GATATGCTAC 8760 TAAATCCGTT TCCTTTCGGT AATACTAACG GCATAATTGA TATGGTTACA TTAGGTTTAG 8820 TTGGTGTATG CAAAACGGGG GATGAAGTAC ATGAACATAT TGATGAAGGT CTGTTTAAAC 8880 GCTTAGGACT ACCAGAATGG CTGATAGCCG ACACACGAGA AACATATATT GAATGTGCTT 8940 TGCGTCTAGC AGAAAACCAT CAAGAACGCC TTGAACTCCG TCGTTACATC ATAGAAAACA 9000 ACGGCTTACA AAAGCTTTTT ACAGGCGACC CTCGTCCATT GGGCAAAATA CTGCTTAAGA 9060 AAACAAATGA ATGGAAGCGG AAGCACTTGA GTAAAAAATA ACGGTTTTTT AAAGTAAAAG 9120 TGCGGTTAAT TTTCAAAGCG TTTTAAAAAC CTCTCAAAAA TCAACCGCAC TTTTATCTTT 9180 ATAACGATCC CGCACGCTGA CAGTTTATCA GCCTCCCGCC ATAAAACTCC GCCTTTCATG 9240 GCGGAGATTT TAGCCAAAAC TGGCAGAAAT TAAAGGCTAA AATCACCAAA TTGCACCACA 9300 AAATCACCAA TACCCACAAA AAA 9323 (2) INFORMATION FOR SEQ ID NO:7: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4287 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7: GATCAATCTG GGCGATATTT TTGCCAAAGG TGGTAACATT AATGTCCGCG CTGCCACTAT 60 TCGCAATAAA GGTAAACTTT CTGCCGACTC TGTAAGCAAA GATAAAAGTG GTAACATTGT 120 TCTCTCTGCC AAAGAAGGTG AAGCGGAAAT TGGCGGTGTA ATTTCCGCTC AAAATCAGCA 180 AGCCAAAGGT GGTAAGTTGA TGATTACAGG CGATAAAGTT ACATTGAAAA CGGGTGCACT 240 TATCGACCTT TCGGGTAAAG AAGGGGGAGA AACTTATCTT GGCGGTGACG AGCGTGGCGA 300 AGGTAAAAAC GGCATTCAAT TAGCAAAGAA AACCACTTTA GAAAAAGGCT CAACAATTAA 360 TGTGTCAGGT AAAGAAAAAG CTGGGCGCGC TATTGTATGG GGCGATATTG CGTTAATTGA 420 CGGCAATATT AATGCCCAAG GTAAAGATAT CGCTAAAACT GGTGGTTTTG TGGAGACGTC 480 GGGGCATTAC TTATCCATTG ATGATAACGC AATTGTTAAA ACAAAAGAAT GGCTACTAGA 540 CCCAGAGAAT GTGACTATTG AAGCTCCTTC CGCTTCTCGC GTCGAGCTGG GTGCCGATAG 600 GAATTCCCAC TCGGCAGAGG TGATAAAAGT GACCCTAAAA AAAAATAACA CCTCCTTGAC 660 AACACTAACC AATACAACCA TTTCAAATCT TCTGAAAAGT GCCCACGTGG TGAACATAAC 720 GGCAAGGAGA AAACTTACCG TTAATAGCTC TATCAGTATA GAAAGAGGCT CCCACTTAAT 780 TCTCCACAGT GAAGGTCAGG GCGGTCAAGG TGTTCAGATT GATAAAGATA TTACTTCTGA 840 AGGCGGAAAT TTAACCATTT ATTCTGGCGG ATGGGTTGAT GTTCATAAAA ATATTACGCT 900 TGGTAGCGGC TTTTTAAACA TCACAACTAA AGAAGGAGAT ATCGCCTTCG AAGACAAGTC 960 TGGACGGAAC AACCTAACCA TTACAGCCCA AGGGACCATC ACCTCAGGTA ATAGTAACGG 1020 CTTTAGATTT AACAACGTCT CTCTAAACAG CCTTGGCGGA AAGCTGAGCT TTACTGACAG 1080 CAGAGAGGAC AGAGGTAGAA GAACTAAGGG TAATATCTCA AACAAATTTG ACGGAACGTT 1140 AAACATTTCC GGAACTGTAG ATATCTCAAT GAAAGCACCC AAAGTCAGCT GGTTTTACAG 1200 AGACAAAGGA CGCACCTACT GGAACGTAAC CACTTTAAAT GTTACCTCGG GTAGTAAATT 1260 TAACCTCTCC ATTGACAGCA CAGGAAGTGG CTCAACAGGT CCAAGCATAC GCAATGCAGA 1320 ATTAAATGGC ATAACATTTA ATAAAGCCAC TTTTAATATC GCACAAGGCT CAACAGCTAA 1380 CTTTAGCATC AAGGCATCAA TAATGCCCTT TAAGAGTAAC GCTAACTACG CATTATTTAA 1440 TGAAGATATT TCAGTCTCAG GGGGGGGTAG CGTTAATTTC AAACTTAACG CCTCATCTAG 1500 CAACATACAA ACCCCTGGCG TAATTATAAA ATCTCAAAAC TTTAATGTCT CAGGAGGGTC 1560 AACTTTAAAT CTCAAGGCTG AAGGTTCAAC AGAAACCGCT TTTTCAATAG AAAATGATTT 1620 AAACTTAAAC GCCACCGGTG GCAATATAAC AATCAGACAA GTCGAGGGTA CCGATTCACG 1680 CGTCAACAAA GGTGTCGCAG CCAAAAAAAA CATAACTTTT AAAGGGGGTA ATATCACCTT 1740 CGGCTCTCAA AAAGCCACAA CAGAAATCAA AGGCAATGTT ACCATCAATA AAAACACTAA 1800 CGCTACTCTT CGTGGTGCGA ATTTTGCCGA AAACAAATCG CCTTTAAATA TAGCAGGAAA 1860 TGTTATTAAT AATGGCAACC TTACCACTGC CGGCTCCATT ATCAATATAG CCGGAAATCT 1920 TACTGTTTCA AAAGGCGCTA ACCTTCAAGC TATAACAAAT TACACTTTTA ATGTAGCCGG 1980 CTCATTTGAC AACAATGGCG CTTCAAACAT TTCCATTGCC AGAGGAGGGG CTAAATTTAA 2040 AGATATCAAT AACACCAGTA GCTTAAATAT TACCACCAAC TCTGATACCA CTTACCGCAC 2100 CATTATAAAA GGCAATATAT CCAACAAATC AGGTGATTTG AATATTATTG ATAAAAAAAG 2160 CGACGCTGAA ATCCAAATTG GCGGCAATAT CTCACAAAAA GAAGGCAATC TCACAATTTC 2220 TTCTGATAAA GTAAATATTA CCAATCAGAT AACAATCAAA GCAGGCGTTG AAGGGGGGCG 2280 TTCTGATTCA AGTGAGGCAG AAAATGCTAA CCTAACTATT CAAACCAAAG AGTTAAAATT 2340 GGCAGGAGAC CTAAATATTT CAGGCTTTAA TAAAGCAGAA ATTACAGCTA AAAATGGCAG 2400 TGATTTAACT ATTGGCAATG CTAGCGGTGG TAATGCTGAT GCTAAAAAAG TGACTTTTGA 2460 CAAGGTTAAA GATTCAAAAA TCTCGACTGA CGGTCACAAT GTAACACTAA ATAGCGAAGT 2520 GAAAACGTCT AATGGTAGTA GCAATGCTGG TAATGATAAC AGCACCGGTT TAACCATTTC 2580 CGCAAAAGAT GTAACGGTAA ACAATAACGT TACCTCCCAC AAGACAATAA ATATCTCTGC 2640 CGCAGCAGGA AATGTAACAA CCAAAGAAGG CACAACTATC AATGCAACCA CAGGCAGCGT 2700 GGAAGTAACT GCTCAAAATG GTACAATTAA AGGCAACATT ACCTCGCAAA ATGTAACAGT 2760 GACAGCAACA GAAAATCTTG TTACCACAGA GAATGCTGTC ATTAATGCAA CCAGCGGCAC 2820 AGTAAACATT AGTACAAAAA CAGGGGATAT TAAAGGTGGA ATTGAATCAA CTTCCGGTAA 2880 TGTAAATATT ACAGCGAGCG GCAATACACT TAAGGTAAGT AATATCACTG GTCAAGATGT 2940 AACAGTAACA GCGGATGCAG GAGCCTTGAC AACTACAGCA GGCTCAACCA TTAGTGCGAC 3000 AACAGGCAAT GCAAATATTA CAACCAAAAC AGGTGATATC AACGGTAAAG TTGAATCCAG 3060 CTCCGGCTCT GTAACACTTG TTGCAACTGG AGCAACTCTT GCTGTAGGTA ATATTTCAGG 3120 TAACACTGTT ACTATTACTG CGGATAGCGG TAAATTAACC TCCACAGTAG GTTCTACAAT 3180 TAATGGGACT AATAGTGTAA CCACCTCAAG CCAATCAGGC GATATTGAAG GTACAATTTC 3240 TGGTAATACA GTAAATGTTA CAGCAAGCAC TGGTGATTTA ACTATTGGAA ATAGTGCAAA 3300 AGTTGAAGCG AAAAATGGAG CTGCAACCTT AACTGCTGAA TCAGGCAAAT TAACCACCCA 3360 AACAGGCTCT AGCATTACCT CAAGCAATGG TCAGACAACT CTTACAGCCA AGGATAGCAG 3420 TATCGCAGGA AACATTAATG CTGCTAATGT GACGTTAAAT ACCACAGGCA CTTTAACTAC 3480 TACAGGGGAT TCAAAGATTA ACGCAACCAG TGGTACCTTA ACAATCAATG CAAAAGATGC 3540 CAAATTAGAT GGTGCTGCAT CAGGTGACCG CACAGTAGTA AATGCAACTA ACGCAAGTGG 3600 CTCTGGTAAC GTGACTGCGA AAACCTCAAG CAGCGTGAAT ATCACCGGGG ATTTAAACAC 3660 AATAAATGGG TTAAATATCA TTTCGGAAAA TGGTAGAAAC ACTGTGCGCT TAAGAGGCAA 3720 GGAAATTGAT GTGAAATATA TCCAACCAGG TGTAGCAAGC GTAGAAGAGG TAATTGAAGC 3780 GAAACGCGTC CTTGAGAAGG TAAAAGATTT ATCTGATGAA GAAAGAGAAA CACTAGCCAA 3840 ACTTGGTGTA AGTGCTGTAC GTTTCGTTGA GCCAAATAAT GCCATTACGG TTAATACACA 3900 AAACGAGTTT ACAACCAAAC CATCAAGTCA AGTGACAATT TCTGAAGGTA AGGCGTGTTT 3960 CTCAAGTGGT AATGGCGCAC GAGTATGTAC CAATGTTGCT GACGATGGAC AGCAGTAGTC 4020 AGTAATTGAC AAGGTAGATT TCATCCTGCA ATGAAGTCAT TTTATTTTCG TATTATTTAC 4080 TGTGTGGGTT AAAGTTCAGT ACGGGCTTTA CCCACCTTGT AAAAAATTAC GAAAAATACA 4140 ATAAAGTATT TTTAACAGGT TATTATTATG AAAAACATAA AAAGCAGATT AAAACTCAGT 4200 GCAATATCAA TATTGCTTGG CTTGGCTTCT TCATCGACGT ATGCAGAAGA AGCGTTTTTA 4260 GTAAAAGGCT TTCAGTTATC TGGCGCG 4287 (2) INFORMATION FOR SEQ ID NO:8: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4702 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8: GGGAATGAGC GTCGTACACG GTACAGCAAC CATGCAAGTA GACGGCAATA AAACCACTAT 60 CCGTAATAGC ATCAATGCTA TCATCAATTG GAAACAATTT AACATTGACC AAAATGAAAT 120 GGAGCAGTTT TTACAAGAAA GCAGCAACTC TGCCGTTTTC AACCGTGTTA CATCTGACCA 180 AATCTCCCAA TTAAAAGGGA TTTTAGATTC TAACGGACAA GTCTTTTTAA TCAACCCAAA 240 TGGTATCACA ATAGGTAAAG ACGCAATTAT TAACACTAAT GGCTTTACTG CTTCTACGCT 300 AGACATTTCT AACGAAAACA TCAAGGCGCG TAATTTCACC CTTGAGCAAA CCAAGGATAA 360 AGCACTCGCT GAAATCGTGA ATCACGGTTT AATTACCGTT GGTAAAGACG GTAGCGTAAA 420 CCTTATTGGT GGCAAAGTGA AAAACGAGGG CGTGATTAGC GTAAATGGCG GTAGTATTTC 480 TTTACTTGCA GGGCAAAAAA TCACCATCAG CGATATAATA AATCCAACCA TCACTTACAG 540 CATTGCTGCA CCTGAAAACG AAGCGATCAA TCTGGGCGAT ATTTTTGCCA AAGGTGGTAA 600 CATTAATGTC CGCGCTGCCA CTATTCGCAA TAAAGGTAAA CTTTCTGCCG ACTCTGTAAG 660 CAAAGATAAA AGTGGTAACA TTGTTCTCTC TGCCAAAGAA GGTGAAGCGG AAATTGGCGG 720 TGTAATTTCC GCTCAAAATC AGCAAGCCAA AGGTGGTAAG TTGATGATTA CAGGTGATAA 780 AGTCACATTA AAAACAGGTG CAGTTATCGA CCTTTCAGGT AAAGAAGGGG GAGAGACTTA 840 TCTTGGCGGT GATGAGCGTG GCGAAGGTAA AAATGGTATT CAATTAGCGA AGAAAACCTC 900 TTTAGAAAAA GGCTCGACAA TTAATGTATC AGGCAAAGAA AAAGGCGGGC GCGCTATTGT 960 ATGGGGCGAT ATTGCATTAA TTAATGGTAA CATTAATGCT CAAGGTAGCG ATATTGCTAA 1020 AACTGGCGGC TTTGTGGAAA CATCAGGACA TGACTTATCC ATTGGTGATG ATGTGATTGT 1080 TGACGCTAAA GAGTGGTTAT TAGACCCAGA TGATGTGTCC ATTGAAACTC TTACATCTGG 1140 ACGCAATAAT ACCGGCGAAA ACCAAGGATA TACAACAGGA GATGGGACTA AAGAGTCACC 1200 TAAAGGTAAT AGTATTTCTA AACCTACATT AACAAACTCA ACTCTTGAGC AAATCCTAAG 1260 AAGAGGTTCT TATGTTAATA TCACTGCTAA TAATAGAATT TATGTTAATA GCTCCATCAA 1320 CTTATCTAAT GGCAGTTTAA CACTTCACAC TAAACGAGAT GGAGTTAAAA TTAACGGTGA 1380 TATTACCTCA AACGAAAATG GTAATTTAAC CATTAAAGCA GGCTCTTGGG TTGATGTTCA 1440 TAAAAACATC ACGCTTGGTA CGGGTTTTTT CAATATTGTC GCTGGGGATT CTGTAGCTTT 1500 TGAGAGAGAG GGCGATAAAG CACGTAACGC AACAGATGCT CAAATTACCG CACAAGGGAC 1560 GATAACCGTC AATAAAGATG ATAAACAATT TAGATTCAAT AATGTATCTA TTAACGGGAC 1620 GGGCAAGGGT TTAAAGTTTA TTGCAAATCA AAATAATTTC ACTCATAAAT TTGATGGCGA 1680 AATTAACATA TCTGGAATAG TAACAATTAA CCAAACCACG AAAAAAGATG TTAAATACTG 1740 GAATGCATCA AAAGACTCTT ACTGGAATGT TTCTTCTCTT ACTTTGAATA CGGTGCAAAA 1800 ATTTACCTTT ATAAAATTCG TTGATAGCGG CTCAAATTCC CAAGATTTGA GGTCATCACG 1860 TAGAAGTTTT GCAGGCGTAC ATTTTAACGG CATCGGAGGC AAAACAAACT TCAACATCGG 1920 AGCTAACGCA AAAGCCTTAT TTAAATTAAA ACCAAACGCC GCTACAGACC CAAAAAAAGA 1980 ATTACCTATT ACTTTTAACG CCAACATTAC AGCTACCGGT AACAGTGATA GCTCTGTGAT 2040 GTTTGACATA CACGCCAATC TTACCTCTAG AGCTGCCGGC ATAAACATGG ATTCAATTAA 2100 CATTACCGGC GGGCTTGACT TTTCCATAAC ATCCCATAAT CGCAATAGTA ATGCTTTTGA 2160 AATCAAAAAA GACTTAACTA TAAATGCAAC TGGCTCGAAT TTTAGTCTTA AGCAAACGAA 2220 AGATTCTTTT TATAATGAAT ACAGCAAACA CGCCATTAAC TCAAGTCATA ATCTAACCAT 2280 TCTTGGCGGC AATGTCACTC TAGGTGGGGA AAATTCAAGC AGTAGCATTA CGGGCAATAT 2340 CAATATCACC AATAAAGCAA ATGTTACATT ACAAGCTGAC ACCAGCAACA GCAACACAGG 2400 CTTGAAGAAA AGAACTCTAA CTCTTGGCAA TATATCTGTT GAGGGGAATT TAAGCCTAAC 2460 TGGTGCAAAT GCAAACATTG TCGGCAATCT TTCTATTGCA GAAGATTCCA CATTTAAAGG 2520 AGAAGCCAGT GACAACCTAA ACATCACCGG CACCTTTACC AACAACGGTA CCGCCAACAT 2580 TAATATAAAA CAAGGAGTGG TAAAACTCCA AGGCGATATT ATCAATAAAG GTGGTTTAAA 2640 TATCACTACT AACGCCTCAG GCACTCAAAA AACCATTATT AACGGAAATA TAACTAACGA 2700 AAAAGGCGAC TTAAACATCA AGAATATTAA AGCCGACGCC GAAATCCAAA TTGGCGGCAA 2760 TATCTCACAA AAAGAAGGCA ATCTCACAAT TTCTTCTGAT AAAGTAAATA TTACCAATCA 2820 GATAACAATC AAAGCAGGCG TTGAAGGGGG GCGTTCTGAT TCAAGTGAGG CAGAAAATGC 2880 TAACCTAACT ATTCAAACCA AAGAGTTAAA ATTGGCAGGA GACCTAAATA TTTCAGGCTT 2940 TAATAAAGCA GAAATTACAG CTAAAAATGG CAGTGATTTA ACTATTGGCA ATGCTAGCGG 3000 TGGTAATGCT GATGCTAAAA AAGTGACTTT TGACAAGGTT AAAGATTCAA AAATCTCGAC 3060 TGACGGTCAC AATGTAACAC TAAATAGCGA AGTGAAAACG TCTAATGGTA GTAGCAATGC 3120 TGGTAATGAT AACAGCACCG GTTTAACCAT TTCCGCAAAA GATGTAACGG TAAACAATAA 3180 CGTTACCTCC CACAAGACAA TAAATATCTC TGCCGCAGCA GGAAATGTAA CAACCAAAGA 3240 AGGCACAACT ATCAATGCAA CCACAGGCAG CGTGGAAGTA ACTGCTCAAA ATGGTACAAT 3300 TAAAGGCAAC ATTACCTCGC AAAATGTAAC AGTGACAGCA ACAGAAAATC TTGTTACCAC 3360 AGAGAATGCT GTCATTAATG CAACCAGCGG CACAGTAAAC ATTAGTACAA AAACAGGGGA 3420 TATTAAAGGT GGAATTGAAT CAACTTCCGG TAATGTAAAT ATTACAGCGA GCGGCAATAC 3480 ACTTAAGGTA AGTAATATCA CTGGTCAAGA TGTAACAGTA ACAGCGGATG CAGGAGCCTT 3540 GACAACTACA GCAGGCTCAA CCATTAGTGC GACAACAGGC AATGCAAATA TTACAACCAA 3600 AACAGGTGAT ATCAACGGTA AAGTTGAATC CAGCTCCGGC TCTGTAACAC TTGTTGCAAC 3660 TGGAGCAACT CTTGCTGTAG GTAATATTTC AGGTAACACT GTTACTATTA CTGCGGATAG 3720 CGGTAAATTA ACCTCCACAG TAGGTTCTAC AATTAATGGG ACTAATAGTG TAACCACCTC 3780 AAGCCAATCA GGCGATATTG AAGGTACAAT TTCTGGTAAT ACAGTAAATG TTACAGCAAG 3840 CACTGGTGAT TTAACTATTG GAAATAGTGC AAAAGTTGAA GCGAAAAATG GAGCTGCAAC 3900 CTTAACTGCT GAATCAGGCA AATTAACCAC CCAAACAGGC TCTAGCATTA CCTCAAGCAA 3960 TGGTCAGACA ACTCTTACAG CCAAGGATAG CAGTATCGCA GGAAACATTA ATGCTGCTAA 4020 TGTGACGTTA AATACCACAG GCACTTTAAC TACTACAGGG GATTCAAAGA TTAACGCAAC 4080 CAGTGGTACC TTAACAATCA ATGCAAAAGA TGCCAAATTA GATGGTGCTG CATCAGGTGA 4140 CCGCACAGTA GTAAATGCAA CTAACGCAAG TGGCTCTGGT AACGTGACTG CGAAAACCTC 4200 AAGCAGCGTG AATATCACCG GGGATTTAAA CACAATAAAT GGGTTAAATA TCATTTCGGA 4260 AAATGGTAGA AACACTGTGC GCTTAAGAGG CAAGGAAATT GATGTGAAAT ATATCCAACC 4320 AGGTGTAGCA AGCGTAGAAG AGGTAATTGA AGCGAAACGC GTCCTTGAGA AGGTAAAAGA 4380 TTTATCTGAT GAAGAAAGAG AAACACTAGC CAAACTTGGT GTAAGTGCTG TACGTTTCGT 4440 TGAGCCAAAT AATGCCATTA CGGTTAATAC ACAAAACGAG TTTACAACCA AACCATCAAG 4500 TCAAGTGACA ATTTCTGAAG GTAAGGCGTG TTTCTCAAGT GGTAATGGCG CACGAGTATG 4560 TACCAATGTT GCTGACGATG GACAGCAGTA GTCAGTAATT GACAAGGTAG ATTTCATCCT 4620 GCAATGAAGT CATTTTATTT TCGTATTATT TACTGTGTGG GTTAAAGTTC AGTACGGGCT 4680 TTACCCACCT TGTAAAAAAT TA 4702

Claims: CLAIMS What we claim is: 1. A vaccine against disease caused by non-typeable Haemophilus influenzae. including otitis media, sinusitis and bronchitis, comprising an effective amount of a high molecular weight protein of non-typeable Haemophilus influenzae which is protein HMWl, HMW2, HMW3 or HMW4 or a variant or fragment of said protein retaining immunological properties thereof or a synthetic peptide having an amino acid sequence corresponding to that of said protein, and a physiological carrier therefor. 2. The vaccine of claim 1 wherein said protein is HMWl encoded by the DNA sequence shown in Figure 1 (SEQ ID NO:l), having the derived amino acid sequence of Figure 2 (SEQ ID NO:2) and having an apparent molecular weight of 125 kDa. 3. The vaccine of claim 1 wherein said protein is HMW2 encoding by the DNA sequence shown in Figure 3 (SEQ ID NO:3) , having the derived amino acid sequence of Figure 4 (SEQ ID NO:4) and having an apparent molecular weight of 120 kDa.

Inventors: BARENKAMP STEPHEN J, ST GEME JOSEPH WILLIAM III, BARENKAMP, STEPHEN, J., ST. GEME, JOSEPH, WILLIAM, III
Applicants: BARENKAMP STEPHEN J, ST GEME JOSEPH WILLIAM III, BARENKAMP, STEPHEN, J., ST. GEME, JOSEPH, WILLIAM, III
Application year: 1994
Main classification: A61K39
IPC codes: A61K39, C07K14, C12N1, C12N15, C12P21, C12R1